Developments and Challenges: Adapting Continuous Manufacturing for Pharmaceuticals

FDA Initiatives

The United States has experienced a constant increase in drug shortages since 2010, which has caused numerous adversities to health care facilities, clinicians, and patients. Major reasons behind drug shortages include supply chain disturbances, regulatory issues, and manufacturing problems, which are tracked by FDA. In a recent article, FDA’s Center for Drug Evaluation and Research (CDER) encouraged the adoption of new production technologies such as 3D printing and CM as long-term methods to address drug shortages.⁵

CM’s uninterrupted processing improves efficacy and manages variability. The FDA guidelines in Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach, 2004 suggest that using a scientific framework to find ways to mitigate risk, while facilitating continuous improvement and innovation in pharmaceutical manufacturing, is a key public health objective. Thus the chemistry, manufacturing, and controls have shifted to a new risk-based pharmaceutical quality assessment system, and CDER’s Office of New Drug Chemistry has encouraged CM improvements and process analytical technology (PAT).⁶

In a recent blog post, Michael Kopcha, director of CDER’s Office of Pharmaceutical Quality (OPQ), stated that “CM allows for more nimble testing and control that can help reduce the likelihood of manufacturing failures.” FDA’s Emerging Technologies Team (ETT) is available to help companies interested in implementing CM.⁷ Also, in the article Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing, Sau (Larry) Lee, Ph.D., from OPQ, talks about the initiatives FDA has taken to facilitate the industry’s implementation of CM for improving product quality and addressing many underlying causes of shortages and recalls. Further, FDA provides resources and information for transition from batch to CM. FDA also provides funds for research in this area and for conducting internal research on risk associated with CM for better assessment of related technologies. There has been significant interest among pharmaceutical companies in FDA’s Emerging Technology Program (ETP) for CM.⁸

Reports suggest that some pharmaceutical companies have already benefitted from FDA’s initiative programs by adopting CM to increase production capacity in a more efficient manner, to lower the cost of production, and to improve overall yield. Vertex Pharmaceuticals switched to CM and received an approval from FDA in July 2015 for Orkambi (lumacaftor/ivacaftor) to treat cystic fibrosis.⁹

Eli Lilly and Company has invested approximately $40 million in a new continuous active pharmaceutical ingredient (API) manufacturing setup in an existing facility in Kinsale, Cork County, Ireland. In April 2016, FDA approved another drug manufacturing change from batch to CM process for Prezista (darunavir), a drug for HIV-1 infection manufactured by Janssen Supply Chain in its Puerto Rico plant. This advancement in the manufacturing process was facilitated by FDA’s guidelines from September 2017, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, drafted by ETT to help pharmaceutical companies implement a variety of technological advancements.⁹

FDA has also recently awarded a $4.4 million contract to Continuus Pharmaceuticals to develop a science- and risk-based approach to monitor and improve drug quality through integrated CM. The Continuus team is developing a fully automated, end-to-end, integrated continuous pilot plant, expected to be fully functional soon, that will test relevant regulatory principles, including real-time release and traceability.¹⁰

Adapting CM Processes

The CM process has gained a lot of traction in manufacturing pharmaceuticals in large volumes, particularly for solid oral dosage forms. Combined with PAT, which allows simultaneous and integrated quality monitoring and control, it is equipped with capabilities for monitoring, analyzing, and controlling the manufacturing system from time to time. For example, in a simple blending process, where the endpoint is to obtain a homogenous blend of drug and excipients, PAT monitors the blending process in real time and determines whether the blend meets product specifications, thus saving time in getting the product to market.

Some major players in the pharmaceutical industry have already begun developing methods to set up CM facilities. Janssen and Johnson & Johnson are working on an ambitious project of incorporating CM in their range of pharmaceutical products with an aim to “manufacture 70% of their highest-volume products using CM within the next eight years, increasing yield of the drug product by reducing waste by 33%, and reducing manufacturing and testing cycle time by 80%.”¹¹

In 2015, Pfizer and GlaxoSmithKline teamed up to develop a CM process for oral solid dosage forms. They designed a prototype called Portable, Continuous, Miniature, Modular system. As per the claims, the new system would require only two-thirds of the space required for a conventional facility and would take only a year to set up compared to the conventional production line, which takes at least two to three years to set up.¹²

Challenges

Other industries such as food, chemicals, and petrochemicals have adapted continuous process technologies to manufacture their products, but the pharmaceutical industry still seems skeptical about the whole idea of transforming from batch to CM. Batch manufacturing is a traditional method with excessive capacity of processing in pharmaceutical facilities, which makes it difficult to let go and allows companies to resist upcoming changes and improvements.

Although CM may help save revenue loss on production, the initial cost for transition from traditional manufacturing to a continuous process remains high. Michael Rooney from Genesis mentioned that the cost savings alone may not be a good enough rationale to justify the cost of transferring a production process from batch to continuous. This includes the upfront cost of equipment, time required in the process of change, and reregistering the products with FDA, thus leading to loss of production. “However, most companies that want to reduce cost and increase overall product quality will try to apply continuous processing in the near term,” Rooney concluded.¹⁰

In another major challenge, CM is undesirable for novel methodology and formulations due to its lack of flexibility. Switching from one drug to another and changing the manufacturing process is extremely challenging for CM. The pharmaceutical industry is bursting with a variety of drugs under development, with limited success potential for clinical and commercial use. For such products, huge investments are required to set up CM, which is not feasible for smaller organizations. In some cases, if more drug product is required, a continuous process line cannot possibly be altered to process the drug in shortage.¹³

Contract manufacturing organizations (CMOs), where the production requirements change occasionally based upon market requirements, are more inclined to follow a batch manufacturing process. Using this method, CMOs can make specific amounts of a certain product and then alter their manufacturing process according to market demands.¹³

Further, CM facilities have significantly diverse requirements, making it difficult to set up a robust CM unit in the same premises as the batch unit. For instance, a vertically designed building is preferred for CM, making it easier to feed raw materials from the top and collect final product from the bottom. Flow of the process runs from top to bottom, where the final product can be directly packed and shipped. Along with the outflow of final product, inflow of raw material is also crucial. To ensure continuous movement of raw material, storage facilities like silos are required. Also, to transfer and handle material in large amounts, heavy equipment is needed. The process also requires large database management and storage space for data generated from real-time analytical technology. Thus, CM needs a lot of investment both for initial setup and future maintenance costs.

After setup, emphasis shifts to maintenance. Being a closed system, scheduled equipment cleaning is a colossal task. In some cases, the equipment needs to be completely disassembled, cleaned, swabbed, dried, and reassembled. While current cleaning protocols require manual cleaning, industries are developing automated techniques such as the Clean-In-Place system. Vertex Pharmaceuticals recently reported considerations of automated washers at its Boston facility to significantly reduce cleaning time.¹⁴ Still, some equipment cannot be maintained for continuous use, such as a tablet press, which is built using stainless steel of different grades, and the force applied in the process generates stress on the stainless steel causing wear and tear that might affect the physical attributes of the final tablet.¹⁵

In CM, drugs are continuously produced in a fully automated system that requires fewer people to run it, unlike a batch process which requires extensive process handling. CM is controlled and monitored with the help of new technology systems which require personnel with a different set of skills, such as IT specialists who can program software and run the analysis, and scientific statisticians who can evaluate, interpret, and manage data. Automation and continuous processes make close monitoring imperative. “You can’t have someone running the process from a control room. You need the process engineer on the floor, giving close attention to several different unit operations at the same time,” noted José Luis Santos, head of operations for drug product CM at Hovione, a contract manufacturer that is partnering with Vertex.¹⁴ Hiring personnel with the required skills and training them based on the manufacturing process are an important part of the transition and cannot be overlooked.

FDA is working toward implementation of the CM process using a science- and risk-based approach. FDA is also encouraging industries to consider and amalgamate CM in their current processes. Despite these efforts, there are minimal regulations and industrial guidelines to support CM. According to FDA, product quality should remain the same as in batch processing. However, because CM is a highly automated process with faster process dynamics, it is hard to run quality checks and analysis, which necessitate analytical methods such as PAT for more frequent measurements and real-time monitoring. These advanced and novel methods make the transition more challenging. Deviation from conventional methods needs to be handled differently, and manufacturing changes need proper management. Just like the pharmaceutical industry, regulatory bodies are trying to
adjust and modify regulatory guidelines to support CM.¹⁶

Emerging Technologies

Recent advancements in CM in the pharmaceutical industry have led to development of new technologies to support relevant processes. Two of these are hot melt extrusion and 3D printing technologies.

Hot melt extrusion: Hot-melt extrusion is a continuous process in which the pharmaceutical materials are extruded through a barrel under high temperature and pressure to give a uniformly dispersed product. It is an emerging process in the pharmaceutical industry and is primarily used for CM and scaling up production. An additional benefit to this technique is to enhance the solubility of poorly soluble drugs by forming amorphous solid dispersions of drug and excipients with higher drug loading and content uniformity. Most of the drug substances are highly lipophilic with poor water solubility in their crystalline form with limiting dissolution and oral bioavailability. Hot melt extrusion has emerged as a popular technique to solve this problem by forming amorphous solid dispersions.

Printing technology: 3D printing is an upcoming method for continuous processing that can be adapted for fully automated operations. It is a type of additive manufacturing in which tablets are built layer by layer with the help of binding agents that bind the material together into a solid dosage form. It can also be used to build tablets with multiple drugs in a single dose. APIs in a multilayer tablet can be used to develop targeted and controlled-release drug products. In 2015, FDA approved a 3D-printed drug, levetiracetam (Spritam—Aprecia). Aprecia Pharmaceuticals used a powder bed and inkjet 3D printing technology called Zipdose to prepare Spritam. In this technology, a powder layer is laid along a conveyer belt on which a binding liquid is printed according to the shape of the dosage form, after which another layer of powder is added and so on. The number of repetitions depends on the size of the tablet and drug dose. The precise amount of material is added using continuous-run equipment. “Using continuous 3D printing technique, Aprecia can print tens of thousands of tablets a day on a single printer,” said Tim Tracy, Aprecia’s chief executive.¹⁷ 

Conclusions

CM has been recognized as a more efficient and time-saving process than batch processing. It can offer better quality and control over the manufacturing process. Over the past decade, with advancement in science and technology, new techniques such as PAT and quality by design have been developed as more proficient approaches toward scientific and regulatory readiness for CM. Recent developments have also encouraged FDA to try to make CM more accessible for the pharmaceutical industry. Even then, flexibility is a priority for manufacturers for making CM play a greater role in large-scale commercial manufacturing. In the case of early stage development of new drugs with greater market uncertainty, they will still have batch processing as their preferred mode of production, making it easier to work on a small scale for implementing day-to-day changes in the process of drug development. Manufacturers must explore all possibilities and be open to new technology but also to taking a realistic approach for ensuring the most effective, practical, and cost-effective route to pharmaceutical manufacturing.

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