The Trouble with PDE
Several companies have shifted their cleaning validation concept toward the use of HBEL- (Health-Based Exposure Limit), mostly PDE-based residue and carry-over limits. Basis for this is EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012), commonly discussed as „the PDE guideline“.
At first this guideline had caused much turmoil in a multitude of pharmaceutical quality systems. The reason was that only few knew how to really obtain those PDE values. Not for lack of calculation formula (that is given in the guidance), but for lack of NOAEL and / or LOEL data serving as key input for those calculations. The drug developing companies had little issues with this, since they themselves typically establish the very NOAEL and LOEL data during preclinical studies. But for generic drug manufacturers and even contract manufacturers it was not that easy.
And so PDE – for a few years – became a true pet peeve for compliance officers and cleaning validation stakeholders.
PDE: Well Meant – but Poorly Done?
Today many companies have adjusted, some even to a degree that they do not employ traditional limit calculations such as 10ppm or 0.1% dose criteria at all any more. PDE has evolved from a nuisance at first, to now being almost a defense against having to calculate the typically tougher traditional limits. And not surprising: supervising authorities / gmp-inspections go right along with it.
But here comes the fun fact: PDE – as one of several options for HBEL calculation – is itself not meant to be used as a carryover or residue limit(!). …who says so…? Well, EMA does. In other words: The vast majority of stakeholders got the EMA guidance not right. Already in April 2018 EMA published a Q&A document on the „PDE-Guideline“, where it plainly states:
“Although the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) may be used to justify cleaning limits, it is not intended to be used to set cleaning limits at the level of the calculated HBEL.“
So the statement is clear: HBEL-based and thus also PDE-based limits may be used to justify cleaning limits. But the PDE-value is not supposed to be the limit itself(!). It is really important here to not rip part 1 of the sentence (subordinate clause) off of the following second part – the main clause (grammar helps tremendously when reading regulatory texts…).
EMA goes on to explain i.e. to imply, that alert limits for cleaning are expected to be used, and that those alert limits are typically the traditional limits – not the PDE based limit itself. In other words: Whoever applies PDE-based limits alone cannot really be in compliance with EMA requirements on this matter.
That´s the truth. And this has consequences because it means that PDE first caused much unnerving and trouble – and then it was – in a sense – „taken back“ or defused a bit by EMA. First it was a deficiency to not employ PDE, now – if we are honest – it is a defciency to only employ PDE.
And honestly: this was to be expected or quite obvious. Most of the time the PDE-calculated limits are a lot more lenient than the results from traditional limit calculations. Sometimes the allowable residues according PDE-based calculations are so high that one would not even need to swab or rinse a manufacturing equipment to detect that residue – it would boldly sit there on the equipment surface and one could scrape off the allowable amount by hand.
So what is the PDE good for if it is not really desired to be applied as a cleaning limit?
In a nutshell, EMA states that PDE can be employed to justify the handling of product or susbstance residues depending on the PDE range a product or material falls into. For this EMA shows this diagram (originally from ISPE):
Figure 1: PDE-Range diagram as reproduced from ISPE within the EMA Q&A document on the HBEL guideline. EMA/CHMP/CVMP/SWP/169430/2012. Questions and Answers on health-based exposure limits and cross-contamination (europa.eu), accessed Nov 9, 2021.
The problem ist that only little solid instruction for the actual use of this PDE continuum is provided here. So, not only is it almost ironic that PDE value based cleaning limits are mandated all over the globe now inspite of not being mandated by EMA. But what is more: EMA does not even expressly tell us how exactly we are supposed to apply them. The tone is: Use PDE values in a … thingie-ma-jigger… risk based way. But frankly (@EMA): everyone knows that. But it does not help to act on this requirement.
The PDE Status Quo and Bottom Line?
Companies have made due with EMA´s elusiveness on this. Everyone finds their own way of trying to convince their regulators and local inspectors that all is fine in their establishment. Some do PDE categories and treat each category with certain control measures. Others simply apply PDE as a general carryover limit. Again others simply apply much stricter limits to all processes and materials and in this way get rid of this whole PDE discussion altogether.
So in the end the PDE-guideline served more as an expression of a regulatory timidity of letting traditional limits continue to be the best practice. For the industry it first and foremost meant more cost because they had to somehow make sense of this. And for the patients it is conceivable that the PDE-guideline actually increased the risk for inadequate carryover amounts where PDE is applied as fact value cleaning limit.
I wonder how much one earns at EMA…
written by: Dr. Dietmar Gross (pharmacist & Senior Consultant)
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