Although continuous manufacturing is common in other industrial production, such as food processing and petrochemicals, batch manufacturing is the prevailing method of production for the pharmaceutical industry. Led by a quality-by-design (QbD) paradigm, innovation in process analytical technology (PAT), and regulatory support to modernize pharmaceutical manufacturing, however, the pharmaceutical industry is advancing select projects in continuous manufacturing.DCAT Value Chain Insights (VCI) examines the latest developments.

The prospect of reducing manufacturing footprints, achieving greater flexibility, increasing efficiency, and reducing costs makes continuous manufacturing a potential consideration for pharmaceutical companies. With installed capacity now heavily centered on batch manufacturing, however, the industry is moving gradually to continuous manufacturing for active pharmaceutical ingredients (APIs) and solid dosage products. Companies are applying continuous manufacturing for select projects with some having a vision to integrate API and drug product manufacturing in one continuous mode.

Several companies are advancing continuous manufacturing projects. In May 2015, Johnson & Johnson’s Janssen furthered its strategic partnership with the Rutgers University School of Engineering by providing over $6 million to expand ongoing research efforts supporting the company’s introduction of continuous manufacturing techniques for pharmaceuticals. The funds from Janssen, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, will increase research and development efforts at the Rutgers Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) over the next several years. The center is helping Janssen transition several products to continuous manufacturing, including developing a specially designed manufacturing line at a Janssen facility in Puerto Rico.

The Rutgers ERC, established nine years ago with funding from the National Science Foundation and a consortium of more than 40 companies within the pharmaceutical sector, is an academic-based research organization dedicated to modernizing pharmaceutical manufacturing of solid oral dose medications. The funding from Janssen represents an expansion of an arrangement that began five years ago and that focuses on technical development of continuous processing.

As part of this collaboration, Rutgers engineers designed and built a full production-scale continuous direct compression solid oral dosage manufacturing facility, which was used as the model for the Janssen production line in Puerto Rico and is also being used as a model by other pharmaceutical manufacturers. This direct compression tableting line, located at the engineering school campus in Piscataway, New Jersey, has now been expanded to also include wet and dry granulated products and can accommodate tests of multiple production routes under automated control for optimal product and process design.

Since the center’s founding, researchers at Rutgers have worked in collaboration with industry and its partner universities Purdue, the New Jersey Institute of Technology, and the University of Puerto Rico to develop an understanding of the science that goes into designing and operating continuous pharmaceutical manufacturing systems for solid oral dosage forms. The Rutgers group has been researching a wide variety of areas, including powder processing and materials properties, process modeling and control, and in-line process analytical technology in order to design and implement robust and reliable manufacturing processes that meet the quality standards of a regulated industry at lower cost.

In October 2014, GlaxoSmithKline (GSK) announced it was investing £19 million ($29 million) in a continuous manufacturing facility in Jurong, Singapore. The facility is scheduled to be completed in 2015 and become operational in the first quarter of 2016 and produce one of GSK’s key respiratory APIs. The facility is part of GSK’s multi-year partnership with Singapore’s Economic Development Board (EDB) for developing sustainable and green manufacturing in Singapore. GSK has three manufacturing facilities in Singapore (Jurong, Quality Road, and Tuas).

Vertex Pharmaceuticals, a Boston, Massachusetts-based pharmaceutical company, has developed several manufacturing processes to produce commercial quantities of co-formulated lumacaftor/ivacaftor, including a process utilizing continuous manufacturing technology as well as a traditional batch manufacturing process. Ivacaftor is the API in Vertex’s Kalydeco, a drug to treat cystic fibrosis (CF). It was approved in 2012 in the United States and European Union as a treatment for patients with CF six years of age and older who have the G551D mutation in their CFTR gene. In November 2014, Vertex submitted a new drug application to the US Food and Drug Administration (FDA) and a marketing authorization to the European Medicines Agency for lumacaftor in combination with ivacaftor in patients with CF twelve years of age and older who are homozygous for the F508del mutation in their CFTR gene. In July 2015, Orkambi (lumacaftor 200 mg/ivacaftor 125 mg) was approved by the FDA for this indication, and a decision by the EMA is expected later this year. The target patient population, which provides an indication of potential supply needs, is niche. Vertex believes that there are approximately 22,000 patients with CF twelve years of age and older who are homozygous for the F508del mutation in North America, Europe and Australia, including approximately 8,500 in the United States and approximately 12,000 in Europe. In 2015, Vertex initiated a Phase III development program for its CF investigational drug candidate, VX-661, in combination with ivacaftor in patients with CF twelve years of age and older, including patients who are homozygous for the F508del mutation in their CFTR gene and patients who have one copy of the F508del mutation in their CFTR gene (heterozygous).

Vertex established manufacturing capabilities at its third-party manufacturer in the United Kingdom, which was used to produce a portion of the clinical trial supplies for its Phase III clinical trials of lumacaftor in combination with ivacaftor and is establishing continuous manufacturing capabilities and seeking validation for these capabilities at its facility located in Boston, Massachusetts. The goal of continuous process manufacturing is to reduce material waste and cycle times and improve yield, which may result in reduced cost, reduced development and production timelines, lower inventories and increased market response flexibility. Vertex says it is the first company to seek approval for a NDA using a continuous manufacturing process. A third-party manufacturer also is producing commercial quantities of co-formulated lumacaftor/ivacaftor using the traditional batch manufacturing process that the company designed. Vertex said it expects to use a traditional batch manufacturing process to obtain a supply of VX-661 to be used in its Phase III clinical trials of VX-661 in combination with ivacaftor. If the company successfully commercializes VX-661 in combination with ivacaftor, it plans to produce the commercial supply of VX-661 using a continuous manufacturing process, according to the company’s 2014 annual filing.

When applied, continuous manufacturing is applied through using it in parallel synthesis in API manufacturing or applying it for specific unit operations and coupling them, such as in solid dosage manufacturing. A visionary approach, using an end-to-end approach that integrates both drug substance and drug product manufacturing is being considered by Novartis, through an initial 10-year, $65-million collaboration that the company formed with the Massachusetts Institute of Technology (MIT) in 2007, with the goal of developing a fully integrated platform for continuous manufacturing that would integrate drug-substance manufacturing with finished drug-product manufacturing. Under the program, initial research is conducted primarily through PhD programs at MIT laboratories and involves MIT faculty members, students, postdoctoral fellows, and staff scientists. Novartis then applies the research to industrial-scale projects and pilots new manufacturing processes using its own pharmaceutical products.One example of a prototype process was for the development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical. The prototype plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets (1).

References
1. P. Heider et al., Org. Process Res. Dev. 18 (3), 402-409 (2014).