I’m sometimes asked if a transferred process should use the same Critical Performance Parameters (CPP), Proven Acceptable Range (PAR) and Normal Operating Range (NOR) parameters and values and what parameter values should be used in the manufacturing documentation for such a newly transferred process. Two questions really, but my thoughts are as below.
Transfer the same Critical Process Parameter (CPP) & values?
The first reaction may well be “yes – of course” – it’s the same product and manufacturing method that is being transferred, but that’s not always the case. While it may well be the case if you are using the same equipment, and the process is being manufactured at the same scale. And some parameters such as temperature or pressure transfer can easily. However, even with the best of intentions there are often minor differences in some of the equipment used between sending and receiving sites (previous sites older equipment size / model is not available or been “updated”) and sometimes the opportunity to “optimise” the process during the transfer is irresistible.
While the fact that a particular CPP’s will remain a CPP unless the process has been redesigned some CPP’s will likely have changed value (e.g. mixing speed and mixing time of a liquid mixer) due to even slight differences in impeller type or positioning, in such cases the Proven Acceptable Range (PAR) values will have to be re-evaluated.
Even more so for more significant changes such as a change from say a vertical to a horizontal granulator, as previous studies cannot be used to establish the new PAR values for each affected CPP’s and need to be re-established experimentally. This can be done by performing a series of engineering runs but it is more usual to study only the affected unit operations in separate “support studies” such as separate granulation or mixer studies to define new PAR values. The material produced during these studies is often used to demonstrate comparability with material previously produced.
If process changes are significant enough, then full scale demonstration batches may have to be run and CPP’s re-evaluated. Such batches and studies are often call bridging studies (linking both previous manufacturing parameters with the new ones).
I’ve often seen the Normal Operating Range (NOR) values being transferred as well as part of the technology transfer process, and to my mind this is an absolute no–no. Why? Well in part it just demonstrates that the receiving site doesn’t understand what this value represents or how it is established.
The NOR is primarily the natural variation around the target value as experienced at the receiving site. This natural variation is unique to the receiving site equipment, environment, process control systems and people and it has to be measured at each specific manufacturing site. The NOR is not a limit, it’s a measure of that sites capability and acts an alert point for that site’s specific manufacturing process. During technology transfers it is often the case that the receiving site does not have sufficient specific process experience to assign this at the receiving site.
NOR values are used to:
- Account for natural variation.
- Ensure that any abnormal variations are detected before they become a process issue.
- Demonstrate process control.
NOR values can be assessed at the receiving site by using:
- Data from engineering runs.
- Previous equipment history (historical data).
If the receiving site has no history to base a value on, the sending sites NOR value may give a guide (but general guide only as a starting point.
- Manufacturers equipment capability specifications.
- Instrument / sensor calibration accuracy.
And should take into account:
- Some computer-controlled equipment can maintain tight limits.
- If manual input is required, the difficulty, ease or precision capability of the operation.
- The accuracy / resolution of equipment / readout of equipment or analytical instrument
- Digital / rounding up-down errors.
Although NOR values cannot (or should not) be transferred, they are usually required as part of the receiving sites product licence application. This means that it is incumbent of the receiving site to monitor the process variations during pre-PPQ studies and runs (and indeed during PPQ runs) to determine the NOR values for their equipment on their site.
Once you have transferred a process, what process parameter value should you include in your manufacturing documents?
Each PAR value will have its own study derived or product specification target value. However, these target values are usually expressed as a range of values e.g. net weight +/- 10g in manufacturing documentation.
It is not advisable to use the CPP / PAR limits as the range value, this builds in too much process variability to start with while at the same time using any NOR values means that you will be working at the edge of the process equipment’s limits and is likely to cause unnecessary out of specification alerts or deviations. The manufacturing documentation values you use should be tight enough to ensure control, but wide enough so that natural variation doesn’t result in unnecessary deviations.
So any value between the PAR and the NOR value would be OK. The temptation is to use a documented value as close to NOR as possible – but that can be counterproductive. A + 5% over the NOR value or +10% against target value might be used as a starting point. Sometimes it may be best to go a little wider provided PAR isn’t approached / exceeded. You can always tighten this once process experience is gained and NOR value understood it’s much easier to justify the tightening of a range than seeking to widen it, (as my QA colleagues I’m sure will agree). Widening limits after process failures will only leave you open to accusations of widening it to avoid deviations.
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.