We probably all understand what scaling-up a process is – increasing the batch size to reap the economies of scale and also many of the problems that have been encountered along the way. But scaling down? Why?
The reasons for scaling-down a process are not always understood. By scaling down, I mean replicating the larger process at a smaller or even laboratory / benchtop scale. Why would we do that and what relevance is this to technology transfer?
Scale-down principles have long been used to evaluate and understand how a process will be carried out and the parameters that surround the process. Scaling down is thus mimicking the larger scale process using a smaller process.
There are three main reasons for scaling down a process:
1. Process development, which usually starts with small scale processes on the laboratory bench. As many technology transfer practitioners have found out – unfortunately often the hard way, many process characteristics and parameters do not scale up well or are difficult to achieve, such mixing or heating parameters.
In order to assess the effects (or limitations) of the larger scale process without the time and cost implications of running multiple large-scale batches, the processes can be performed at much smaller scale simulating the larger scale parameters of rate of temperature rise or mixer shear rate.
The result of such scale-down studies can mean optimisation of large batch processes can be performed quicker and cheaper, ensuring technology transfer can be “right first time”.
Scaled-down processes can be used to either mimic the whole operation or just specific unit operations.
2. Troubleshooting of larger scale processes (where for instance 10 or more small scale fermentations can be run on the bench at a time), especially useful if raw materials are expensive or in short supply or perhaps is just not practically feasible. Scaled down studies can be used to examine parameter values experienced as a result of out-of-specification or process deviations.
3. Process Development, that is to create and validate small scale models of the full-scale process to perform process development as a pre-cursor to technology transfer and gain an understanding of the processes Design Space and to achieve reliable process characterization. This is becoming increasingly common in the development and technology transfer of biological products.
The results of scaled down studies can be used to support process validation studies, and product licence applications, however in such cases it is important that any scaled-down models “should account for scale effects and be representative of the proposed commercial process” [ICH Q11], in effect the small scale model must be validated or “scientifically justified” against actual results obtained from the larger batch size.
Regulatory guidance on the use of small scale models is provided by ICH and FDA documents:
ICH Q8 (Pharmaceutical development) – an assessment of the ability of the process to reliably produce a product of the intended quality can be provided.”
ICH Q9 Quality Risk Management – to assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and technology transfer.”
ICH Q11 Development and Manufacture of Drug Substance – a scientifically justified model can enable a prediction of product quality, and can be used to support the extrapolation of operating conditions across multiple scales and equipment.”
FDA’s process validation guidance -a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process . . . the assurance should be obtained from objective information and data from laboratory-, pilot-, and/or commercial-scale studies.
EMA Notes for Guidance on Process Validation – allows data from small scale studies to be submitted for a marketing authorisation if studies on production scale batches are not available, however it is expected that such studies be linked with available production data.
In some cases (such as viral clearance studies scaled down studies are actually required, ICH Q5A(R1) requires that viral clearance studies can only be performed using qualified scale-down platforms, including chromatography and nanofiltration, in a virology lab located outside the cGMP facility.
About The Author:
Trefor Jones is a technology transfer specialist with Bluehatch Consultancy Ltd. After spending over 30 years in the pharmaceutical / biopharmaceutical industry in engineering design, biopharmaceutical processes, and scale-up of new manufacturing processes, he now specializes in technology transfer especially of biotechnology and sterile products.
He can be reached at trefor ”at” bluehatchconsultancy.com.