Speciality Chemicals Magazine SEP / OCT 2023 | Page 37

A larger set-up for cGMP kilo scale-up is therefore required . The equipment should be capable of producing several kg / day within a 24-hour production cycle ( 24 / 5 or 24 / 7 ) with no events , variances or deviations . This results in an increased rate of consumption of raw materials ( 100 ml / min is 144 L / day ) compared to the benchtop unit . Therefore , larger storage capacity is already required .

Since it is under cGMP , the process must be more controlled with the necessary automation . This typically includes flow rate controls with a feedback loop . The pressure and temperature could still be recorded off gauges or digital displays but in a batch record instead of a lab notebook .

The equipment needs to be qualified like any other cGMP plant equipment , i . e . installation , performance and operational qualification ( IQ , OQ , PQ ). The equipment needs to operate safely for long periods of time and reliably provide product within the quality specifications .

The current practice is to build a skid that is designed and built to specification based on the R & D lab demonstration . The skid is then used for the cGMP kilo scale . Unfortunately , this requires time and can be expensive .

Manufacturing the equipment typically requires six months to a year , depending on the complexity of the skid . Installation and qualification can also take another several weeks before the first batch can be produced . Since the skid is designed for this specific step , it is difficult to use it for a different process , resulting in an accumulation of carts in storage .

It is important that the supply of clinical material occurs quickly using the technology that will be used at commercial scale . It is increasingly difficult to change the process during clinical trials prior to commercialisation . A large economic incentive is needed to change the process especially if it has been filed in multiple countries . Therefore , it is key that the equipment used at kilo and commercial scale are similar and that the process for scale-up is well understood .

A modular approach

Since it takes too long to design , install and qualify equipment for kilo-scale manufacturing , a multi-purpose facility approach for equipment was considered . Instead of building equipment to the optimised chemistry , why not adapt the chemistry to existing equipment ?

In fact , this is the exact same approach that is used in batch manufacturing , where the process is scaled up to existing equipment , and the number of batches and the batch size are adapted to the equipment train . Scale-up from one size to the next only requires a revalidation of the process providing that the sequence and type of steps remains the same .

However , continuous processes are more complex and therefore it would be difficult to have multiple complex skids to address the variety of possible processes without a significant investment . In most cases , the continuous process relies on several inputs of solutions being pumped into a reactor of some design with temperature and or pressure control .

From this observation , we can see that every step of continuous chemistry can be broken down into combinations of several simpler elements or modules . By using this concept , a multi-purpose approach is a lot simpler ( Figure 4 ).

Each module is designed based on a specific unit operation but also includes automation . Each can be designed against preestablished requirements , with specific materials of construction and operating ranges , and the module can be qualified individually like any piece of equipment .

Any modification of the module is handled through the quality system via change control . A library of modules can be easily set up and when a specific process requires a new type of module , design and manufacturing are significantly faster because of the standardisation of the design and the smaller scope . This results in a much lower capex requirement and a lot faster set-up time .

The modules need to be connected to an automation system . Communication is also standardised . Each module is equipped with a single data cable that connects to an automation module ( Figure 5 ). This module in turn is connected to a centralised PLC . The data from the modules is stored in a qualified and validated historian to comply with the data integrity requirements of cGMP manufacturing .

The process is monitored and controlled by operators or chemists via a human-machine interface ( HMI ) specific to the process that can be adapted to each new process in a matter of days . Since each individual

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