Multiplexing sterile injectables manufacturing
Take a deep dive into multiplexing sterile injectables manufacturing by viewing our white paper, Manufacturing Injectables in the Multiplex. It focuses on the approaches and technologies that will help pharmaceutical manufacturers thrive in the current environment, with its smaller target patient populations, uncertain market conditions and other factors.
Last weekend, my wife and I went to the movies. Theatres are very different than they were 20 years ago. We went to a multiplex with four theatres—one showing the latest action blockbuster, one showing a popular comedy and one theatre alternating between two art films. The entertainment industry adapted to become more flexible through the multiplex. It struck me that Pharma could learn from the model to also adapt to changing requirements.
The blockbuster is your company’s lead revenue generator. The art film is a specialty product. The comedy is your lead clinical candidate. Your production schedule operates like a movie theatre to meet demand requirements.
The new pharmaceutical manufacturing facility is like a multiplex, with smaller, more flexible units of production. Scheduling is staggered to allow a smaller staff to handle a consistent level of activity. Standardization allows the blueprint to be applied anywhere in the world.
What is multiplexing?
Pharmaceutical companies are struggling to reconcile their manufacturing infrastructure—built for the blockbuster age—to a higher number of different therapeutics for smaller patient populations.
Multiplexing is configuring drug manufacturing facilities to operate like cinemas—able to produce different drugs in response to market signals. If a drug has rising demand or has clinical trial importance, more of the production schedule is dedicated to it. In multiplexing, the facility, equipment, and its operation are restructured around technologies that are lower cost, flexible, and can be applied in other locations. The operative words for multiplexing are “lean” and “flexible.”
It is a workable model for companies with multi-product portfolios, local production requirements, or a high number of development candidates. Many companies want manufacturing modules that require less infrastructure support for use in developing markets.
Key differences of a multiplex model
Two key differences should be highlighted in comparing a multiplex facility to conventional designs.
1. Smaller units of production that are less expensive to build and operate
“Smaller units of production” describes how production changes from large-unit-volume campaigns to a larger number of smaller campaigns. This reflects the change in market demand for the individual therapies. Every piece of equipment is scaled down to be “right-sized” with the units being produced.
“Less expensive to built and operate” means that facilities and equipment move away from expensive purpose-built solutions to standardized multi-purpose equipment. Custom aseptic filling machines, hard-piped stainless steel bioreactors, and non-ISO vials are all examples of process design choices that do not fit the needs of flexible production.
A supporting ecosystem of technologies and approaches has emerged to support multiplexing, by building facilities faster and enabling more flexible production:
- Modular prefabricated cleanrooms
- Common infrastructure delivered from a centralized location
- Staff cross-trained to monitor and manage different types of automated processes
- Multiple lines of single-use bioreactors
- Single-use aseptic processing devices like connectors, mixers, product bags, and flow paths
- Aseptic filling systems with short changeover times and container / closure flexibility
- Nested ready-to-use containers and closures
- Adaptable inspection, labelling, and secondary packaging machines
2. Production to demand with detailed scheduling
Production quantities originate from forecasts months, or maybe even years, in advance. A company can be left holding huge inventories or underproducing. Both outcomes have major financial consequences. In an environment of more numerous therapeutics, it is preferable to have facilities and equipment that can be allocated to a greater number of smaller batches. A multiplex facility helps companies remain agile by matching production more closely to actual demand.
Typically, a manufacturing team might know their production schedule a month, or a quarter in advance. In a multiplex, production has been reconfigured around flexible production technologies, so batch sizes might vary, and there will definitely be a higher number of batches. Technologies like single-use bioreactors, robotic aseptic filling workcells, ready-to-use nested containers and closures, and flexible secondary packaging and serialization technologies support these changes to production.
Modular units of production in a multiplex facility
Consider a biological multiplex producing multiple antibodies for either biosimilars or innovator biologics for specific patient populations. The upstream and downstream biomanufacturing processes are housed in modular cleanrooms, and share common utilities and cross-trained staff. Instead of transferring the bulk drug to another facility for formulation, aseptic filling, inspection, and secondary packaging, these activities can be performed on-site, housed in their own modules and using the same common utilities and staff.
For the purposes of this discussion, there are two lines of 500 L single-use bioreactors, producing about 2.1 kg of purified antibody per batch. Assume one batch from each 500 L line per week of production. The therapeutic dose for an antibody can be anywhere between 5 and 500 mg per dose, but we will assume 50 mg for our calculations. That means the facility needs to fill about 84,000 containers per week. Easy to do with a single high speed aseptic filling line—if the therapeutics are all packaged into the same format.
But biologics are packaged in a wide variety of container formats. Everything from 1mL staked syringes to 5 mL custom cartridges to 50 mL vials. Aseptic filling lines are a conduit through which containers and closures flow. In this respect, combining robotic systems with ready-to-use nested containers and closures is a huge leap toward production flexibility. Vanrx built the SA25 Aseptic Filling Workcell for these scenarios. A good rule of thumb is one SA25 for every 1000 L of bioreactor capacity.
Of course, few facilities operate on such low volumes, so in a multiplex, several such units operate in parallel. The most efficient, fastest and least expensive path is to scale out, not up. The functional units of the facility can be replicated in parallel as production demands increase, adding either bioprocessing or aseptic filling capacity as required. A true multiplex facility has multiple reactor chains feeding multiple aseptic filling workcells.
Downstream from the bioprocessing and aseptic filling modules, there are shared inspection, serialization, and secondary packaging functions. Like the upstream and primary packaging activities, flexibility is highly valued. Machines and processes used in these areas should also prioritize flexibility. As one example, we recently visited Interpack and saw a new de-nesting / inspection / re-nesting machine. The machine is capable of doing detailed inspections on nested syringes, vials, and cartridges. A single one of these machines could possibly perform all of the inspection activities for a multiplex facility.
Multiplexing with the SA25 Aseptic Filling Workcell
The SA25 Aseptic Filling Workcell is capable of flexibly producing vials, syringes, or cartridges. Since the workcell is a standard design, units can be built and installed in less than a year. This is a similar lead-time to biomanufacturing facilities constructed with modular cleanrooms.
This model allows pharmaceutical companies to add capacity quickly, or to switch production to new products. Multiple units can operate in parallel, providing redundancy and rapid scaling. If this model is executed properly, pharma will begin to look a lot like Hollywood.
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