BP Purified Water in Bulk - Oxidisable Substances vs TOC

GOOD VALIDATION PRACTICE (cGVP) PURIFIED WATER VALIDATION
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Background: At the beginning of developing our purified water system, the purified water generated shall comply BP “Purified Water in Bulk”. Since it is optional for us to choose testing oxidisable substances or TOC, we choose to test oxidisable substance, and the PWS does not have a in-line TOC meter. The purified water is used to manufacture non-sterile oral liquid only.

We are now qualifying the PWS in phase 3. In recent internal discussion, it is suggested to change the testing from oxidisable substances to TOC by purchasing a TOC meter in QC lab (i.e. offline testing).

I would like to know, if we change the test from Oxidisable Substances to TOC, is it required to re-qualify the PWS? If yes, does it mean we need to qualify it again from Phase 1? If no, what recommendation or approach shall we take in order to adopt TOC testing and fade out the Oxidisable Sustances testing?

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Yes. You will have to requalify your PWS (each 'point of use)! But this also means you can ship outside of Britain (North America perhaps where USP specifications are supreme).

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I assume you are using the 3 phase approach to water qualification. (Honestly, I don’t know of any other approach).

You might be able to leverage either phase 1 (static) or phase 2 (in-use) with some sort of documentation saying that “we got XXX for oxidizable substances, which might translate to YYY for TOC”. You might be able to state "from phase 1 and Phase 2, we found that ZZZ locations are worst case for oxidisable substances and oxidisable substances includes TOC (organic carbon is oxidizable, but is more selective than just oxidizable substances), thus we have found the worst case locations (the purpose of Phase 1/2) and will repeat phase 3 testing only.

NOTE: Phase 3 testing often (per ISPE guide, etc.) does not need to test each site. It often tests the worst case site (end of line) each day of testing at a minimum, and then tests other additional sites on a random schedule, and any other sites as required by Phase 1/2 results and risk analysis.

But…to be honest, I really think due to the high risk nature of purified water systems (it is often the single largest constituent/component for bulking/cleaning/operations), leveraging would have to be VERY well documented and defended in order to pass muster in an audit. I think I would only be comfortable with leveraging phase 1, which only buys you maybe 1-2 weeks of testing at most.

Overall, I agree with BoomerChemist, that revalidation will be required. You might want to start parallel validations, one to satisfy the old market (using oxidisable substances) and the another to satisfy the new market (using TOC). Typically this won’t affect commercial launch in a market, as the registration/inspection/approval process in a market often takes longer than the 1+ year to qualify the water system.

Also note, I think you can do clinicals/registration lots “at risk” while still in phase 3 qualification. So again, this won’t impact your overall schedule. Please talk to a regulatory specialist to confirm if this assumption in correct.

This should add more work to sampling and testing, but shouldn’t affect the overall business timelines to launch in new markets.

Also, if your market allows for either testing method, and you want to convert. You might want to continue with your old method, and start over with your new method (so you have qualified both methods), and you can complete the conversion when the new method is complete - thus still being able to move forward with the current method, but transitioning to the new method in 1 year.

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Thanks Boomer_Chemist and Jared.

Since we have initiated Phase 3 testing for 2 months, I am thinking the approach:
If we want to perform TOC test, and finally fade out the OS test, we continue to perform OS for 1 year (as per recommended by WHO TRS970 46th Annex 2). At the same time, we start to perform TOC test for 1 year. When the TOC test result for 1 year is completed and comparable to OS, can I conclude that the result of OS and TOC complied with the BP requirement, and we can eliminate the OS test by means of change control?

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Only if it is allowed by the monograph or if you change/update to a tighter monograph.