Reference standards

[nageshwar]

Hi to all!
We are using reference standards, which are procured from regulatory authorities(EDQM). The reference standard is used for one time and resealed. The question is “how long the ref standard can be used, do they have any shelf life?â€

[grzesiek]

stability data for standards should be available from the manufacturer

[Hollow]

AFAK:
the CRS substances of the Ph.Eur are "valid" with the assigned content only for the mentioned monographs. But then the validity of the batches from EDQM should be stated on the documents which came with the substance.

Otherwise it could be found here:

http://crs.pheur.org/db/index.html

-> search your substance > choose your Batch-Nr for the detail view (batch validty view BVS)
(Maybe there are only the actualy valid batches listet, so if yours doesn't show up, it might no longer be valid for official use)

Home of EDQM-Standards: http://www.edqm.eu/en/EDQM-Reference-Standards-649.html

Ok, this is not necessarily related to the chemical stability but for the legal validity of its use for pharmaceutical testing

[Baxthorpe]

Life gets tedious when you try to examine this as a subject.

Getting a straight answer from anyone is almost impossible about shelf life.

Of course, it depends on the nature of the substance, the mode of packing, and storage conditions.

If you store a vial, unopened, under the conditions indicated, it should still be good if the EDQM site indicates that the same batch is still OK.

You are supposed to open it immediately before use, then use it for the procedures indicated. The content is certified for the substance "as is", so you don't have to consider assaying or moisture content. It is usually packed under nitrogen, to avoid decomposition considerations. The content is certified by taking sample vials from the packed batch, to avoid any confusion.

You opened it, and you've got some left over? There's not enough to check it out, and also use it. It might be possible to use it for identification procedures, it depends on the nature of the beast - eg. codeine phosphate is long-term stable, but tocopherol oxidises.

I once went to a conference lecture where the Australian head of Aspro Nicholas R&D gave a talk on the subject. If you weren't there, you missed the closest thing to an official pronouncement on the subject, because the regulatory authorities have been dodging the subject for years.

What the man said was that Nicholas would buy in a little of the official standard, then use it to verify the standardisation of a batch of in-house material that had been packed in suitable conditions (usually packed under nitrogen into vials, and allowed to stabilise for a week before testing). The house standard was distributed around the world to company QC labs, and samples were re-tested at head office as necessary - the default interval was one year for stable substances.

In this day and age, people would demand short-term confirmation tests to establish that shelf life - so initial tests at 3 months and 6 months would probably be needed to say that future tests should be at 1 year intervals.

Whatever - if you open a vial, its uses are limited to immediate intent for quantitative purposes, and near future for qualitative purposes. At 79€ a vial, it might make economic sense to prepare your own house standards.

[Jackus]

My opinion is that you cannot store opened and again resealed standard and declare it as original. After opening the quality of standard is questionable. If substance you use for standardization is stable, you can make batch of calibration solutions and use it instead of solid matter. But you must have confirmed stability of this solution.
Good approach is to use own "in-house" standard as Baxthorpe wrote. Our company use own "in-house" standards which are verified to the USP or EP standards.

My question is closely related to discussed topic, so I add it here instead of creating a new thread:

We have in-house standard which is refered to USP reference standard. Is there any regulation describing demanded quality of in-house standard compared with official standard (example: assay of in-house standard must be within interval of 98-102%)?
Which limits do you use?

Sorry for my english and thank you for comments and suggestions.
Jack

[Bruce Hamilton]

As reference standards are a major source of revenue for controlling bodies, such as the USP, it's not surprising that they work hard to ensure their products are sold to customers.

If you want evidence, look at the fiasco regarding medical gas testing. The USP initially wanted to mandate that only their reference standards could be used by the several thousand gas manufacturer's sites in the USA.

It was so blatantly self-serving and logistically impossible ( gas standards are usually large cylinders - something the USP couldn't produce, even in low numbers ), that they backed off slightly, but they now have a foot in the door.

There was, a couple of years ago, talk of an alternative, commercial, supplier of USP standards being set up in the USA, but I'm not sure whether it has appeared.

The problem is that most compendia specifically state that the reference material must be used for certification as "USP", and secondary standards are only permitted if the reference material is unavailable. Obviously, manufacturers can use in-house surrogate standards up to that point.

The cGMP rules also support the USP, perhaps the only exception would be real time release testing, as described in Q8-10. From ICH 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€

[Baxthorpe]

Looky, there's a couple of considerations here.

Jackus - the easy answer is that your in-house standards should be selected from material that meets all the requirements of the relevant pharmacopoeia, and from batches that are as fresh as possible when your company "packs them down" into individual vials for in-house standards. The only thing to beware of is trying to use them beyond the approved shelf life for that manufacturer's raw material, as given in their Drug Master File (DMF).

Bruce - I have a friend who used to be very involved with the production of the BP reference standards, so I have some idea of the work that goes into verifying that they are fit for use when sold.
I don't think you are right to call them a major source of revenue - they recover the costs, mostly. Standards have to be tested about 6-8 times more heavily than usually. It is down to achieving results that can be statistically analysed, you need that much data before you can apply a T test and get significant results.

I do think that the USP people are "control freaks" when it comes to specifications.
There was a joint European-US committee on raw materials which was like watching paint dry for years - they didn't come to any conclusions. Then some bright spark said "let's find the points we can agree on", and suddenly there were a few USP materials which would also meet EP specification without comparison of "the books" - but not the other way round. Why?
The USP people insisted on tests for things not covered in the EP - like checking for solvents not used in manufacture "in case they had been spilled on the material in transit". And they are still insisting on stuff like that.
So you can buy a lot of materials to EP spec, and they are as good as USP materials. But if you want to use them in the US, you have to do additional tests, over the certified values.
There's a logic behind the matter - if you are obsessive. For myself, I do not see the logic of testing a consignment of Magnesium Stearate from Europe for chloroform content, just in case someone spilled chloroform on it in transit. But that's how far the "audit trail" extends these days.

In the same vein, there are substances in the USP standards list that are never available. Just try to buy some Mitomycin C standard ... most requests have been going down a black hole since around 1980. No explanations ...
If you do get some, it won't come in a standard USP vial. They can peel the Japanese label off, but if they open the vial they have to work on it ...

Control Freaks don't have to explain themselves ...

Well, Bruce, I've got away with using non-compendial standards to release products. I could probably do it in this day and age, even with the extra paperwork. But there's not much specifically written on how to do it in pharmaceuticals.

Standards, as you say, have to be appropriately prepared, identified, tested, approved, and stored (LOL I used to work with the man that wrote these paragraphs - he used to be The Inspector, and later was a consultant for the company I worked for).

The pharmaceutical industry was not "first in the field" on this. I learned the "how-to" when preparing secondary standards in an aluminium foundry about 35 years ago. The statistics for verifying the testing are laid down in general standards applicable in all civilised places. They don't say pharmaceuticals in the title ...
Identification - the compendial tests are usually adequate.
Preparation - you do your best to pack your "divisions" under uniform conditions, and always perform final testing on the final packed product,
sampling from beginning, middle and end of the packing run.
Storage - the authorities approved the DMF, they won't argue with the conditions it gives if you exceed them for precision of control (eg. 20 degC incubator is usually OK for a lot of things).

All the big companies have had procedures in place for this sort of work for a long time - that's part of how new products get onto the market. Ten years at least before they come off patent? Think about it...

[Bruce Hamilton]

OK, not in any particular order.

A couple of decades ago, I also used to release compendial products using non-compendial standards, and we passed audits OK. However, I'm more interested in whether regulatory auditors in 2009 still allow it - without extensive documentation that would make purchasing standards more cost effective. I'm no longer in that environment.

My understanding is that USP is a privately-owned "not for profit" entity that has aggressively tried to capture reference standard markets - consider the fiasco with medical gases.

The only reason the USP backed off is because they logistically couldn't deliver and the industry responded with the threat of political lobbying. As far as I'm aware, "not of profit" and price-gouging are not mutually exclusive, especially if you have a monopoly. The following is from the first hit of a Google search, but later information should be available... Consider...

For 2001 USP Audit statement, in millions, USP had reference standard sales of $27.0 + $2.7 contribution = $29.70, which equals 65% of total revenue, publications only accounted for $10.5. There were $9.85 expenses listed for their "Division of Standards Development" ( the only line on the expenses that is specially related to standards - rest appear to be drug research and information and various admin activities).

Spending $9.85 million to obtain $29.7 millions isn't very altruistic in my world. No wonder some other firms were trying to get in on the action...

I've previously posted elsewhere on this site about the outrageous behaviour of compendial bodies that can not even agree on coding impurities in API by the same letters, eg USP Impurity C may be Impurity E in EP. They eventually will harmonise ( because it's obvious stupid ), but the concept of the ICH was to reduce that nonsense quickly, however national egos seem to appear quickly.

I agree about the excessive testing, however the introduction of risk analysis a couple of years ago should eventually eliminate some of those spurious controls.

I'd note that the history of detailed quality systems using reference standards goes back at least to the defence industry quality system, which then moved to aerospace/aviation and metallurgical/fuels and other industries and regulators.

Please keep having fun,

Bruce Hamilton

[Baxthorpe]

cccrikey! that is a lot of money! If the UK standards preparation dept. was making that sort of dosh, Gordon Brown would be trying to sell it ...