Bulk filling – market overview (part two)

More Than Just Filling:

From the outset, it might seem that bulk filling could not be a simpler process; you are just going from one large container and filling smaller containers. However, as you start to overlay the requirement to maintain low-bioburden (oftentimes sterility), sufficiently wet the filtration media and prove integrity, minimize non-recoverable volume, to fill the containers accurately and consistently, maintain homogeneity across all containers, all the while keeping meticulous batch records of the process, it is not uncommon to hear of bulk filling processes being described as ’insanely complex’, requiring up to four operators and taking more than 30 hours to complete – a clear constraint on the facility’s throughput. Being asked to increase output – faster batches or more product per batch- with the cost of making mistakes as a backdrop, operators often speak to their elevated stress levels associated with bulk filling. With increased regulatory scrutiny, and every drop of product becoming more valuable, this process step is only going to become more complex.

A Case for Configurable Systems - Meeting Industry’s Current and Future Needs:

Why not just automate? This is the obvious response, but it is important to consider that stationary, repetitive processes are the easiest to automate – and bulk filling does not fit this categorization because bulk fill processes are not ’typical’, their process design is highly variable, and there are a significant, unavoidable human-machine interactions that must take place.

There is currently no set way in industry of how bulk filling is performed. Aside from the different types of containers currently being filled (bottles, 2D, or 3D biocontainer bags), a 100 L batch, for example, is just as likely to be filled into 100 x 1 L containers as it is to be filled into 5 x 20 L containers. Moreover, although low-bioburden or sterile filtration is a key principle of bulk filling, it can be performed in several different ways – capsule size and arrangement (single, serial or parallel). With increasingly more multi-product facilities being built or retrofitted, equipment needs to be flexible to cater to the needs of each process. These subtle differences have significant consequences of mechanical, automation and workflow design.

Furthermore, bulk filling at its core is a facility logistics problem; empty containers are brought into the suite, prepared, and staged, manufacturing details recorded, connected, and filled, weights recorded, labelled, and verified and moved onto storage. ‘Task flow’ during the process is critical and there are many manipulations and interactions operators need to perform over the course of the batch that is in stark contrast to, say, a chromatography process where, once the flow kit is installed and columns connected, it is a relatively ‘stand-off’ process. These large number of operator-machine interactions – e.g. fluid connections, manual filter priming and venting, offline testing and manual record transcription – have a significant impact on the overall process’ ‘risk score’ and calls for a holistic approach that puts the operator at the centre of the design process to minimize the risk of task failure.

It is our observation that current automated bulk filling systems are limited in the number of processes they can address. Given the large design space created by all of the process variability already outlined, it is not hard to understand why certain assumptions need to be made in order to deliver standard equipment within lead time and cost. Anything slightly outside their capabilities, these systems require additional customization at significant cost and time, and still drug manufacturers continue to struggle to utilize the equipment in multi-product facilities because of it now being highly engineered for the requirements of a single process. The flow kits of these systems are often sub-optimally designed from a drainability and recovery perspective, and large quantities of high-value product may be non-recoverable in the flow kits post-use with no elegant way of recovering it in either a low-bioburden or sterile manner - directly impacting the number of patients served per batch.

These ‘standard’ systems, we posit, have focused on minimizing the speed of filling but to the detriment on non-recoverable volumes, configurability (adapting to multiple processes) and an incomplete approach to minimizing process risk. Given the limitations of these automated systems and despite the business need, most drug manufacturers opt for manual processing methods to achieve the flexibility needed to cater for the observed process design variability.

In a highly regulated and fiercely competitive manufacturing environment, drug manufacturing facilities are increasingly being tasked to do ‘more with less’. This has necessitated that drug manufacturers increase operational efficiency by shifting towards flexible and scalable single-use equipment. To meet this challenge, bulk filling systems need to adapt by ⁽¹⁾ focusing on delivering value in the right areas, and ⁽²⁾ becoming more configurable to serve a larger design space.

Join us next week where we review some of the challenges specifically relating to automating the bulk filling process.