Revalidation of chromatography with upstream process change

[shandre]

Can someone help me please. This company wishes to install a larger fermenter than what is being used and a larger primaary clarification chain but the same chromatography colum series. Assume that the process remains the same for the fermentation and primary clarification, what will be some problems and revalidation considerations for the new chromatography status?

Thanks in advance

[Bruce Hamilton]

The proposed changes should have already been subjected to a quality risk assessment, and the risks and consequences of the changes identified and included in the process requalification.

I'm not a fermentation specialist, but some obvious questions would be :-
i- Ia the product a primary or secondary metabolite?.
- Has the innoculation source, number of passages, or ratio changed?.
- Have the fermenter conditions ( shear/aeration/media ) changed?
- Is defined media used?
- Has the fermentation duration changed?.
- Will the primary clarification be more protracted or aggressive.

The answers will help determine what aspects of the chromatography require revalidation. If any of the above ( and many other unasked ) questions take the fermentation outside the scope of the initial validation, further chromatography validation should have been an outcome of the risk assessment.

If the product is a secondary metabolite, the impurity profile may have to be reconfirmed, including identification of additional peaks. If primary, there should be no significant changes in product profile, but that still needs to be confirmed.

Obviously, if the process is unique, you will have to wait until the either commission or process requlaification runs to obtain material to confirm the risk assessment.

If no other significant changes have occured, the first three process validation runs should be used also to confirm both operational and product consistency with previous product.

There are plenty of quality consultants who can advise the preferred course of action, but basically risk assessments must be confirmed by experimental data. If defined media is used, and the process has been scaled elsewhere, the amount of work required should be minimal.

Bruce Hamilton

[shandre]

Thank you.

[shandre]

Thank you.
However, if we assume that there is no change in the fermentation process or the clarification chain except for increase in capacity. How would that impact on the chromatography since the same column series is maintained?

[shandre]

The process is a mammalian cell culture fermentation followed by primary clarification and then a chromatographic purification chain.

Produces a wel-characterised glycosylated protein product

Is reproducible and controlled

Is developed from laboratory validated pilot.

The chromatography operating cycle inludes a gradient elution step

The validated allowable ranges of operation have been separately determined for : column capacity; load rate; allowable number of reuses and hold times.

The existing colum series is used 10 100 % capacity foor 40% of time (i.e the total time for load, wash, elute, clean and re-equilibrate takes 40% of the time available between batches.)

So the intended process change is:
to install a larger fermenter and primary clarification chain but use the same column series.

Hopes the info provides for clarity about the situation.

Thanks in advance for all your assisitance.

[Bruce Hamilton]

The process is a mammalian cell culture fermentation followed by primary clarification and then a chromatographic purification chain.

Produces a wel-characterised glycosylated protein product

Is reproducible and controlled

Is developed from laboratory validated pilot.

The chromatography operating cycle inludes a gradient elution step

The validated allowable ranges of operation have been separately determined for : column capacity; load rate; allowable number of reuses and hold times.

So the intended process change is:
to install a larger fermenter and primary clarification chain but use the same column series.

The major issue remains:-
Does the change to larger fermenters change the product composition in any way that might compromise the ability of the chromatography to purify the product?.

Because changing fermenter size is a major step ( refer my earlier post ) and it seems that you are not using defined media, most regulators would expect to see clear experimental evidence that the product profile and gunk requiring separation have not changed due to the scaleup.

Fermenters produce gunk, and the quality and quantity of the gunk varies according to operational conditions and imputs, including media.

The fact that the laboratory process was validated is only relevent if the scale up process has also been validated to the new size. If you can show that the increased size of the fermenters has no effect on the output, then the chromatography qualification become trivial. If you can't, then you probably are facing a a fairly significant process requalification, with the associated analytical nausea.

All of these aspects should have been identified in the initial risk assessment performed by the quality group.

As I noted above, I'm not an expert on fermentations, but the first question I would ask is, " How do you know that the product and gunk are still identical to the previous material going into the chromatography?.

If you can show it is, then the risk assessment should have indicated that any qualifications of the chromatography, due to the more intense usage, should be minor. The fact that you are using chromatography to purify the product indicates that the unwanted gunk has also to be unchanged to ensure the chromatography is not compromised.

As I stated earlier, fermentation is not my field, there are consultants that specialise in the regulaory control of fermentation-derived products, and they would be the best people to ask.

Bruce Hamilton

[shandre]

Thank you.

[shandre]

Thank you. Your response was quite helpful