Reference Standards for cGMP

[Consumer Products Guy]

OK, reference earlier post to getting information from our QA department.
(1) Are ONLY reference standards purchased from USP itself acceptable to FDA auditors, or are USP grade materials that meet all USP requirements acceptable? For example, USP-purchased NaCl is about $200 per gram, where one can purchase 500 grams of USP grade NaCl for under $30, and we use NaCl for system suitability checking for a cGMP chloride procedure.
(2) And what about reference material supplied by the manufacturer, who assays their material v. USP reference standards and supplies that along with with their certificate of analysis for our files?

Or does USP enjoy this high-priced monopoly?

[JGK]

Working in a GLP environment where the guidelines call for test article/Item characterisation (albeit less stringent than GMP), I have found USP products quite deficient in the documentation.

Especially, with regard to retest or expiry dates and certificates of analysis.

Other chemical manufacurers/suppliers are capable of producing it why can't they.

[Dan]

The USP is not the only source of reference standards and the FDA will accept alternatives. An obvous alternative is the EP/BP. These are usually considered as sources of primary reference standard materials. Your SOP should allow for use of secondary reference materials where the secondary material is qualified using a primary source material.

You can have an in-house reference standard. Where your company may be the manufacturer of the material or you purchase it from an outside source. Either way, you go through procedures to qualify each lot of material for use as a reference standard.

Qualification can be compllicated as there may be many tests to perform: assay, purity, melting point, NMR, MS, polymorphic form, etc. It all depends on the material and your SOP. With all of those tests being required, you can understand why reference materials can be so expensive.

I am not sure who would be an alternative source for NaCl. Check with your suppliers. Maybe they can provide you with a lot of material that can qualify as a reference standard.

The USP doesn't make its own materials. They purchase them, certify them and then sell them as reference materials.

Regards,
Dan

[Bruce Hamilton]

If you report testing to any regulatory authority ( including USP ), you are required to use standards that match their requirements, and are approved by them.

If the monograph say use USP reference standard, you have to use it, if it says you can use a compendial product as a standard, then you can use that instead - but not many monographs do..

I was under the impression that a US firm had recently set up to also provide certified USP standards, but I can't recall the details. I doubt they will be much cheaper, but I could be wrong. I doubt the USP would be the best place to find out about other USP standard providers, maybe a Google search?.

Whilst it's possible to produce/procure standards that might be equivalent, they would still have to be approved by the authority ( the EP lists alternative suppliers for their standards ) and most users will find the minimum energy path is to pay for the standards from the authority. An auditor would become very focused on novel stardards.

There are perceived, and real, issues about standard stability and traceability, hence the long-standing USP monopoly, and short expoiry times. Note that expiry times of batches may be developed as the stability programme continues, hence the CoA expiry issues, and the habit of saying which Lot number is currently valid.

What is irritating is the failure to standardise impurity codes between JP, USP, EP, so users could purchase the standards from other regulatory entities.

Please keep having fun,

Bruce Hamilton

[Consumer Products Guy]

Clarification: for our retail consumer products, there are no USP monographs (they exist for the actives themselves only). we take USP actives and put them into OTC (over the counter) pharmaceuticals, and our haveno official monographs. SO do you mean that if we state in our test procedures exactly what is acceptable, then that's OK?

[Bruce Hamilton]

It's outside my expertise, but my assumption is that if your product does not mention USP, then you would be bound by the cGMP ( ICH Q7 etc., ) reuirements, and not USP, along with any other regulatory controls that may exist.

In the case of cGMP, you have to meet the requirements for Reference standards in Q7, provided the regulators ( such as the FDA ) have not imposed additional restrictions.. It's really the responsibility of your Quality Unit to define the rules that are relevant for your operation, so push them for specifics....

From Q7

" 11.17 Primary reference standards should be obtained as appropriate for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognised source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.

11.18 Where a primary reference standard is not available from an officially recognized source, an “in-house primary standardâ€

[Alfred88]

CP Guy,
We usually buy NaCl primary std from Mallinckrodt (now part of JT Baker).
Price:~$50 for 500g. Check out the spec's in the catalog.