PAR: – Proven Acceptable Range
DSp: – Design Space.
NOR: – Normal Operating Range
In reviewing technology transfer documents, I often see process specifications and Process Parameters (PAR and NOR) values quoted which demonstrate a certain amount of misunderstanding as to what these ranges actually represent.
1) In particular I often see Sending Units (SU) including their process NOR values and see the Receiving Units (RU) using these NOR values in their own process without consideration as to whether they are valid or not.
So, just to be clear, the PAR values are process defined values determined during product development that demote the minimum and maximum values of a particular parameter that have been shown (i.e. proven) to allow the process to remain in control and produce a product within the required specifications and these are perfectly alright to transfer across.
The NOR however is a measure of the variability of the Sending Units own equipment and process as performed at the Sending Units site (defined as describing “a region around the target operating conditions that contain common operational variability – variability that can’t always be controlled) [ref.1]. – and are more than likely to be different from the variability seen at the Receiving Unit. The Receiving Unit cannot simply use the Sending Units NOR values.
e.g. SU vs RU variability. NOR depends on individual sites systems & equipment.
The NOR value cannot be simply risk assessed – granted those parameters which can be designated as CPP, non-CPP, KPP etc can be defined by risk assessment, but the actual values cannot be, the PAR values come from process development, and the NOR values come from RU measurement or experience.
2) I often see identical NOR & PAR values quoted, well the two are not equivalent, and should never be so otherwise it just demonstrates that your process is operating on the known acceptable limits of the process and can thus be regarded as being unstable.
3) As in the diagram above, exceeding the NOR is NOT a deviation or discrepancy unless the PAR is also exceeded, it is merely an observation..
4) process ok if each PAR is within spec.
Another common misconception is that if the process operates on the limits of more than one PAR value but still remain within their individual PAR values then the process can be said to be fully in-control and the product quality will remain acceptable – this is NOT always the case. The limits of each of the PAR values do not take into account any interactions between individual PAR’s. It is probably true though that as long as all the other parameters remain within their NOR values then product quality will probably be maintained. To quote the ICH  “a PAR allows deliberate change in one parameter without changing the others outside their NOR/ target values”
The EMEA  states that “where interaction effects between different parameters exist and the acceptable range for one process parameter depends on the setting of another parameter, the parameters should be included in a Design Space.
Which brings us to the Design Space (DSp). Well, helpfully the International Conference on Harmonisation (ICH) Q8 (R2) defines Design Space as: The multidimensional combination and interaction of input variables (e.g. materials attributes) and process parameters that have been demonstrated to provide assurance of quality. Note the word “demonstrated” is used – not “determined by risk assessment” which means data, usually from product development work, should be used.
This means that the interaction between different parameters has been studied and their interaction determined so that how changes in one parameter can affect the PAR values of another parameter. The PAR of a single parameter alone is not a design space.
The Design Space can sometimes be a difficult concept to grasp at first, but I recently came across a presentation which describes it well and much better than I can do in a short blog, but perhaps this is a subject I can return to later.
However, there are no regulatory requirements to have to define a Design Space.
- Improving the understanding of NORs, PARs, DSp and normal variability of process parameters EMA/604040/2016EMA/CHMP/CVMP/QWP/354895/2017 EMA/CHMP/CVMP/QWP/354895/2017 https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-improving-understanding-normal-operating-range-nor-proven-acceptable-range-par_en.pdf
- ICH Q8R2