By James Netterwald, Ph. D.
The manufacturing of a drug — particularly a biopharmaceutical — is a multistep process that includes biosynthesis, storage, purification, etc. The biosynthesis is performed in a bioreactor of some sort, which is a vessel of a specific size that can range from two liters to upwards of 50,000 liters plus, and is actually performed by a specific kind of cell, be it mammalian, microbial, or insect, that is actually programmed to produce the biopharmaceutical in large quantities. After synthesis, the biopharmaceutical must be purified using a technique known as chromatography, which separates the drug from other components in the cell and in the cell culture medium based on size, charge, polarity, and hydrophobicity characteristics that differentiate it from the rest of the cellular soup. Each of these steps requires contact with some surface that could potentially introduce a contaminant into the drug product that is administered to patients. Materials such as the chromatography column, the storage bag for the material exiting the column, bioreactor vessel, and storage bag for prepurification material all have to be validated according to regulatory guidelines to ensure that it will not, in any way, introduce a contaminant(s) into the drug product at any point during the manufacturing process.
THE DISPOSABLE FACTORY CONCEPT
Validation of every material and piece of manufacturing equipment is an expensive and time-consuming process, costing biopharmaceutical companies and contract manufacturers millions of dollars and delaying time-to-market for a new drug. To reduce the impact of this challenge, manufacturers have moved toward the use of disposable manufacturing equipment — bioreactors, chromatography columns, hold bags for storage, etc. These products are part of a larger concept known as the “disposable factory” or “factory in a box.” These concepts are all part of the Six Sigma lean manufacturing best practices currently taking place in the pharmaceutical industry as well as many other industries. In a disposable factory, a typical biologics production process flows from media made in single-use mixing systems for storage in single-use bags or transfer into single-use bioreactors. The contents of the bioreactor are harvested into single-use mixing bags for clarification, filtration, and subsequent chromatography using buffers made in single-use mixing systems. The purified drug products, post-chromatography, are harvested and the bulk intermediates are both collected in single-use bags for further processing, formulation, or fill. After use, these bags are recycled, incinerated, or collected as medical waste.
Despite being practiced in the biopharmaceutical industry for over a decade now, there is not widespread agreement about the meaning of the disposable factory concept. “I don’t think everyone in the industry has the same definition of the ‘factory in a box’ concept, because there are several different challenges driving interest in this concept,” says Eric Grund, senior director of biopharma applications at GE Healthcare in Uppsala, Sweden. Grund gives several reasons why pharma, and more specifically biopharma, is increasingly focused on agile production operations that necessitate the use of disposable factories. One reason is that the significant increase in titres of products like monoclonal antibodies produced from cell cultures, means that manufacturing operations personnel must make adjustments to downstream systems to keep up with increased upstream production. One way of tackling this challenge is to “plug-in” extra downstream capacity in the form of add-on modules. A second reason is that, with a trend toward smaller patient populations, either because of more personalized therapies or due to competition from second-generation products and biosimilars, smaller batches of certain therapeutics are required. A third pressure is the need for development teams to support as many product candidates as possible through the clinic as attrition rates are still high at this stage. A different set of pressures relates to globalization. Pandemic preparedness and threats from bioterrorism mean that vaccine production has to be fast and flexible in terms of scale-up and geography. Disposables enable producers to meet these challenges in new ways. “For example, we are supporting the industry by creating ready-to-use solutions, for cell culture, chromatography, and filtration, all of which eliminates the need for time-consuming cleaning procedures,” says Grund.
According to Maik Jornitz, group VP of marketing of filtration/fermentation technologies at Sartorius Stedim Biotech in Bohemia, NY, “We see that cleaning, setup, and sterilization time of a tank takes typically around 8 hours. The installation of a single-use bag takes minutes. Furthermore, it requires copious amounts of high purity water and energy to sterilize the vessel [i.e. tank]. There have been studies on the resource consumption (e.g. water, cleaning agents, energy, man hours) of using reusable vessels versus single-use hold bags, and the outcome was favorable for single-use systems. Additionally, facilities using single-use technology turn around [i.e. manufacturing operations settings and equipment can be changed quickly to accommodate the production of a new biopharmaceutical] the facility faster, and therefore gain in productivity.”
QUICK SETUP TIME, INTERCONNECTIVENESS
According to Jornitz, biopharmaceutical companies nowadays are asking for single-use unit operations. There are already commercially available single-use unit operations for media prep, buffer prep, and cell harvest, with some systems ranging in volume from 50 liters to 1,000 liters. He says: “The idea behind these single-use unit operations is that the client can operate them from the moment they are out of the box, reducing setup, sterilization, and cleaning times and resources.”
“The concept of the flexible factory is that you leverage state-of-the-art technologies to quickly design, build, and begin GMP biomanufacturing operations in facilities that anticipate continued changes in scale, scope, or process,” says Jeff Craig, global director of marketing and business development at ATMI LifeSciences in Danbury, CT. “Single-use technologies are making flexible factories a reality. These fast-evolving technologies provide rapid response to the need for process capacity in new or existing space or conversion of existing process or space for a different drug or vaccine.”
According to Christopher Mach, global product manager and marketing manager, Allegro single-use technology systems, at Pall Life Sciences in Port Washington, NY, “For a new process, it takes anywhere from two to four years just to get the manufacturing equipment set up, to validate it, and to begin engineering runs before even thinking about manufacturing. But with single-use technology, you can cut that time by at least 2/3 because you don’t have to worry about some ancillary pieces of equipment or cleaning and validations. You also don’t have to worry so much about your equipment raw materials, which are significant cost problems with the traditional biopharmaceutical manufacturing process.”
Mach adds that Pall has noticed its pharma customers purchasing more single-use products over the last few years. “At first they would order anywhere between 200 and 300 pieces a year. But now they often order more than 1,000 pieces a year for the same system,” says Mach.
In accordance with the disposable factory concept, ATMI has designed its single-use mixers and bioreactors so they can be set up quickly with a minimum footprint. Each of ATMI’s mixing and bioreactor systems incorporate disposable vessels made of the same medical grade flexible film (Integrity TK8 film polymer) with a mixing element enclosed. These “bags” are designed for single-use and have proven to reduce operating expense and contamination risks when compared to stainless steel systems for the same applications. For example, Craig says in the process development and preclinical supply lab of one global biopharmaceutical company, an entire suite of 50 liter, 200 liter, 500 liter, and 1,000 liter stainless steel mixing tanks and all of the associated sterilize-in-place (SIP) and clean-in-place (CIP) plumbing was replaced with one single-use PadMixer (ATMI’s single-use mixer). For just the 200 liter stainless steel mixer alone, cost models considering capital costs, labor costs, consumables costs, throughput, and facilities support (CIP/SIP), have shown the single-use mixer can be operated at an annual savings of $322,000 over 50 cycles.
The latest effort by disposable factory subscribers is to build interconnected single-use unit operations. “Single-use systems are easily integrated in the flexible factory concept since they arrive ready to use with certificates of analysis and are designed to be connected to other units of operation,” Craig says. “The integration of single-use modules is facilitated if the mixing, bioreactor, and storage bags are made from the same film. Certificates of film characterization, sterility, and vessel characterization are provided with each bag and can be referenced or included in batch records. This can translate to substantial savings in time and expense. Once a manufacturer qualifies the film, requalification is not necessary when introducing new vessel sizes, additional production trains, or even new units of operation using the same film. As the flexible factory is commissioned and evolves, the team can implement additional mixing, bioreactor and storage systems and be up and running within a matter of days.”
In summary, single-use disposable factories have increased the efficiency of biopharmaceutical manufacturing by eliminating the need to clean and sterilize manufacturing equipment, thereby reducing the overall cost of manufacturing and shortening time-to-market for many biopharmaceuticals.