Bulk Filling – Market Overview (part one)
December 14, 2022
State of the industry:
Over the last 20 years, there has been a rapid growth in the development of therapeutic molecules and biologics including recombinant proteins, monoclonal antibodies and, most recently, viral vectors and mRNA based gene therapies and vaccines. To improve access to these life-changing therapies, manufacturers have looked to increase productivity, optimize the use of process equipment, and improving, or safeguarding product quality.
Whilst the focus of improvement measures has been directed towards process intensification using bioreactors, tangential flow filtration (TFF) and chromatography equipment to better support commercial-scale manufacturing, one vital step in the manufacturing process has sadly been neglected accepting process risk and product loss at a critical point. By not giving bulk filling equal consideration, many manufacturers have unfortunately missed a key section in the manufacturing workflow and have overlooked the impact of bulk filling on the process productivity. Significant improvement in the areas of suite turnover, process step yield and process risk could all be unlocked if the challenges associated with bulk filling can be solved.
Focusing on “Herbie”:
The objective of commercial-scale biologics manufacturing is to manufacture a product as fast and as cost-effective as possible while maintaining product quality. Improving the speed and cost of manufacturing needs a holistic approach and, typically, involves analyzing the entire workflow. As complex as the biologics manufacturing process is, it can be broken down into a series of dependent steps and activities, one of which acts as a constraint upon the entire process. This is the Theory of Constraints conceived by Dr. Eliyahu Goldratt and popularized by his novel, “The Goal”, in the 1980s. The big idea of this theory is that improvement effort should be directed towards the top priority – namely the current constraint. The novel’s protagonist draws a parallel between a production process and that of a Boy Scout hiking troop supervised by only one adult. The objective is that the group needs to hike as quickly as possible to reach their campsite before dark while staying close together ensuring everyone’s safety. The speed of the entire troop is linked to that of one boy, Herbie, and the story goes on to describe the discovery and implementation process the troop follows to lighten Herbie’s backpack and distribute it over all members in order to reach their destination as fast as possible. In this example, the objective centered around speed, but it must be emphasized here that the objective(s) may be different dependent on the environment, business goals and problem definition.
A subtlety often missed when applying the theory is that the constraint may ‘shift’ to a different process step as the constraints are reduced. Those familiar with Lean Six Sigma tools may use this approach when charting the contribution of various factors to the nominated problem using a Pareto chart. In reality, not all contributing factors may be addressable in the same way or at the same speed but being aware of the total set empowers action and improvement. So, while focusing on the areas of facility utilization, process agility, upstream productivity and downstream optimization advances the industry, this progress has exposed further opportunities.
Current bulk filling practices limit progress at this point in the process and even investment to support this step may bring limited benefits to the overall facility throughput without a rethink.
Bulk filling is the process of dividing a large volume of product into smaller containers. In a biotechnology context, it is the critical management of process fluid – drug substance, cell culture media or buffer - usually involving a sterile filtration step or at the very least controls to minimize and control bioburden. It is mainly associated with the accurate filling of multiple 2D biocontainer bags or bottles in the 500 mL to 20 L (nominal) range and is not the same as the filling of syringes, vials or ampules that are common in fill-finish processes. Although bulk filling is strongly linked to the (fluid) management of drug substance following final concentration/diafiltration, it is also an essential workflow step in buffer and media processing as well as cell banking activities.
For the past 10-15 years, polycarbonate bottles have been the container of choice in bulk filling operations. For all their benefits in robustness, bottles suffer from three unavoidable problems owing to their design; (1) they need to be opened, filled and closed under a laminar air flow cabinet to maintain low-bioburden, (2) their design makes them bulky to ship and store, and (3) freezing product in bottles is time consuming and pose rick in forming concentration gradient. A growing trend, however, is the transition from bottles to 2D biocontainer bags owing to the advances in film as well as significant benefits in higher packing/storage densities and plate freezers offering greater levels of scalability and tighter process control when freezing high value drug substance.
In the context of drug substance handling, the importance of bulk filling cannot be overstated; it is the last step in the (drug substance) manufacturing process, handling purified product that is the result of tremendous effort and cost. There are no second chances at this stage. Once filled, these containers may be frozen for short or long-term storage and will eventually be transported to the drug product facilities for final formulation (if required) and filling into vials, syringes, or ampules.
Bulk filling is performed to solve two inventory management problems associated with any supply chain: risk and better matching supply with demand. Where patients’ lives are concerned and ensuring product is made available when needed most, disruptions to the supply of drug substance are not acceptable. From a risk perspective, dividing the product into smaller lot sizes allows for the risk of disruption owing to, for example, container integrity breach to be minimized. With the correct processes in place, it is not uncommon for drug substance to be stored for up to 5 years at ultra-low temperatures. Once formulated however, shelf-life does become a determining factor and spoilage of high-value therapies negatively impacts a drug manufacturers’ bottom line. Mismatches in demand and supply are inevitable but, with smaller lot sizes, it does become easier for drug product facilities to better minimize quality risks, meet demand and reduce the risk of spoilage.
In our next blog in this series we review the complexities of bulk filling.
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Giridaran Ganesan, Global Product Manager- Modular Bioprocess Systems
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