From: B.Hamilton@irl.cri.nz (Bruce Hamilton)
Newsgroups: sci.chem
Subject: Re: USP 23 meaning?  Please help.
Date: Sat, 26 Sep 1998 19:44:59 GMT

"Emre" <biotech@idirect.com> wrote:

>Can someone help me understand what is implied/meant by
>USP 23 etc.  If a company is selling a fine chemical drug or other
>reagents and they suggest that it complies with USP 23 or any
>other USP value what does this mean to the buyer that would
>use it for research purposes?

The USP, BP, and EP grades mean that the chemical has been tested
to the specifications of the specific pharmacopeia ( US, British,
or Euopean ). There has been a move towards standardising the
specifications, but for most drugs, they are different - either
in the test procedures required, the methodology of the test
procedures, or the acceptable limits.  You have to look at
each monograph to find the details, and your local pharmacist or
hospital laboaratory should be able to point you towards who
holds copies. The best way to find out whether a chemical is, or
has been, available in pharmaceutical grade it to look in " The
Extra Pharmacopeia " by Martindale, as it lists which national
pharmacopeia drugs appear in.

>Is this USP 23 equivalent to purchasing a fine chemical that is
>ACS or ultrapure grade from Sigma, Fisher or any other company?

No. The tests for pharmaceutical grade chemicals are different
to those for chemical reagents. In general, the presence of
anything that might have harmful biological activity, such as
heavy metals, closely related compounds, or solvents, is controlled
in pharmaceuticals, and there may even be biological assays as
well as the chemical assays. Pharmaceutical assay limits are
often broader ( 98-101% ) than analytical grades ( 99.5-100 %)
- because the range of tests are intended to identify typical
undesirable impurities expected from the approved production
processes.

>And where can I learn more about these conventions, including the
>BP # convention.

The following is an edited post of mine earlier this year:-

Grades of chemicals are defined by their specifications, and each
chemical has a monograph that usually details certain properties
( appearance, solubility , spectral ), the purity and impurity
specifications, and the analytical procedures used to confirm that
the chemical meets the full specification.

A confounding factor is that many specifications are national, eg
the US pharmaceutical grade of a drug may establish different assay
and impurity limits than the British, European, or Japanese.
There has been a concerted effort to reduce the differences.

Another factor is that specifications can change with time, and
it's important to state which version of the specification the
product complies with. I once had to taste a couple of crystals
of strychnine as the monograph used the shape and bitter taste
as one of the identification tests, and the last very of an
accepted pharmacopeia was from the 1910s.

It will often be the case that food grade will be able to be used
for pharmaceutical grades, but not always - as there may be components
in the food grade that adversely affect stability or effectiveness
of products that the pharmaceutical grade could be used in - that's why
each batch of chemicals have to be fully tested for each of the
specifications the producer wishes to claim compliance for.

Naturally, it's also possible for each grade to specify different
properties or impurities - depending on the end use. Technical
grades are often loosely defined ( colour, loss on drying, ash,
purity ) by the manufacturers and simply agreed between vendor
and purchaser, although some industry standards do exist, such as ASTM.

In the case of food or pharmaceutical grades, the specified impurities
could include residual levels of toxic solvents, toxic elements
( especially heavy metals ), and bioactive impurities. The
specifications are usually defined in monographs written in pharmacopia
or codex.

For analytical grades, the specified impurities are often at 10-1000 ppm
levels, could include species that would interfere with the use of the
chemical in analytical or synthetic procedures by reacting in the same
way as the analyte, and the specifications are usually defined by the
manufacturers ( such as BDH "Analar" ) or chemical institutions ( such
as ACS ).

Molecular biology grades may be defined by the presence of enzymes or
inhibitors that could affect cell culture, as well as bioactive
impurities. Chromatography grades are often defined by their optical
properties (UV) and residues after evaporation, and may be less pure
than analytical grade. Trace analysis grades often have the same
impurities as listed in the analytical grade specified at lower
(sub ppm) levels. There are many other specialist grades, such as
veterinary, semiconductor, microscopy, synthetic, and spectroscopic
grades - each defining criteria that are important for the
specific end use.

Note that chemical supply companies such as Aldrich-Sigma, Lancaster,
with purchase smaller quantities of research chemicals to their own
specifications - which are often just the spefication of the people
producing the chemical, and which usually are just a purity with some
instrumental( NMR or HPLC ) confirmation of identity. Such chemicals
are often called " research " grade, and are often very variable in
quantity, with "typical" specifications  ( rather than actual batch
analyses ) being given in the catalogue.

Note that these "research" chemicals can often contain large amounts of
impurities - such as water, inorganics, or organics - as the tests used
( NMR and HPLC ) may not detect all impurities, and they are not
assayed against standard properties or reference materials. If an
experiment is turning to custard, check reagents - and don't assume
that labelled research chemicals are adequate. In general, research
chemical grades are unacceptable for pharmaceutical or food use
- because their production process has not been approved, but they
are often fine for general laboratory work.

Suppose we take a simple chemical - such as salt. A salt producer
wants to get the best price for their product. In general, for many
chemicals, the price increases with the level of purity - or the
number and/or reduction of specified impurities. For sodium chloride,
the following applied from one local supplier. Note that the most,
expensive grade isn't always the highest purity, but often is the
grade that has the impurities well characterised.
                                           Minimum   Tests    Relative
                                           Purity   Specified   Price
Technical                                    -         0          1
Laboratory ( aka General Purpose ) Reagent  99.5       6         1.5
Pharmaceutical                              99.5      10         1.5
Analytical                                  99.9      17          2
Molecular Biology                           99.5       8          4
Chromatography                              99.9      11          5
Trace Analysis                              99.5      26         34

There is no general rule that enables users to predict whether one
grade will be accepatble as another grade, as the method of preparation
can define the specifications the product may satisfy, and the producer
will attempt to match their product to the highest value specification
they can sell it as complying with.

Before GMP appeared, it was not uncommon to find that a manufacturer
would blend product batches to ensure that the maximum amount of
final product was produced that just complied with the specification.
If the specification calls for 99.5%, then everything above 99.55%
was effectively being given away. Under GMP, all product batches
have to be able to be traced, and blending records maintained - thus
diluting pharmaceutical grade with veterinary grade can be detected.

It's not possible to make general pronoucements about the relative
relationships between various grades of chemicals without first
consulting the all the monographs involved. For a time, the
"reducing sugars" identification test in the European Pharmacopia
monograph for sucrose was so severe that no commercially-available
bulk grade would pass - not even food, analytical, or trace analysis
grades - which was nonsense.

Note that it's possible for chemical assays to have acceptable limits
of 98.5 - 101.5% - not every assay method is accurate to 0.01%, and
some biological assays can have accepatble ranges from 80-120%.

Whilst the sodium chloride pharmaceutical and GPR specifications
may be similar - and one product may be sold as complying with both,
the same is not true for disodium disulphite. There is no general
substitution of grades, because each monograph may even specify
different analytical procedures for the same analyte in the chemical,
and the chemical has to be completely retested in accordance with each
specification.

As many commercial products only have a few processes, then it's
likely the impurity mix can be similar for commercial products,
and the additional costs of specialist grades may exist because of
the additional processing to remove/reduce specific undesirable
impurities that are important to end users  - who will pay a premium
price - such as for the removal of UV-absorbing impurities from HPLC
and spectroscopic grade solvents, even if the assay purity is reduced
compared to chemical grades.

Some "technical" or "laboratory (GPR)" grades can be fairly pure
and cheap if they are used in bulk by multiple industries, and
it's not uncommon for chromatography grades of popular solvents
to be cheaper than other grades, solely because of the volume
used has resulted in economies of scale. Often, industrial
use can greatly reduce the price of a chemical, one recent
example being MTBE ( methyl tertiary butyl ether ) as an alternative
for diethyl ether in the laboratory, and also as a useful HPLC solvent.

Anybody who purchases one grade and uses it as another grade
in a marketed product, without retesting to the full specification
for the marketed grade, would face severe penalties. Obviously, that
prohibition doesn't apply to users substituting grades for their
own use in a laboratory.

In some cases, such as for ethanol here in New Zealand, the only
approved grade for food use is the distilled azeotrope produced from
fermentation - and it must not be made by mixing anhydrous ethanol
with water, because of the possibility of traces of whatever chemical
was used to make anhydrous product by breaking the azeotrope ( such
as benzene ).

The easiest way to investigate the link between specification and price
is to obtain a catalogue from a supplier such as Baker or BDH, and
look at the specifications and prices, and also compare those
laboratory chemical prices with the bulk chemical prices for
technical and/or food/pharmaceutical grades reported in the
Chemical Marketing Reporter.

The best way is to obtain the specifications or monograph for all the
grades of products you are considering purchasing, and comparing them
line by line.

     Bruce Hamilton

From: B.Hamilton@irl.cri.nz (Bruce Hamilton)
Newsgroups: sci.chem
Subject: Re: USP material question
Date: Sat, 06 Nov 1999 06:49:28 GMT

EO wrote:
> Here is the scenario:
> Do manufacturers first make a high purity of
> material and then test this particular batch
> to pass certain tests in the given USP
> standard?   And if this passes the test one
> can call it USP grade.  Or is there much
> more to it?

In the good old days that indeed was how grades
were determined. Make the product, then test and
sell to the highest spec ( Usually pharmaceutical,
then the cheaper veterinary, then technical grade).
For chemicals, analytical grade, followed by reagent
grade, followed by technical grade.

I once worked for a company that tested all the
raw material products, and would blend different
grades to achieve maximum volume of lowest ( but
passable ) specification, and then retest.

These days, with the advent of GMP, such practices
are not permitted, you have to trace ( and have
documentation that traces ) raw materials
to origin - with manufacture also complying with
strignent process controls to ensure the product
is not containimated with unusual nasties. a

Blending to lower specification is no longer
permitted. Also, I suspect vet grade would now
be of similar price to pharmaceutical, whereas it
used to be 25-50% of the cost.

Chemical grades can be funny, with specialist
grades ( super pure for trace analysis ) can
be many times more expensive, but actually less
pure, just that known undesirable impurities have
been removed to make the product suitable for
specific types of analysis or use. It's not
possible to assume that certain grades can be
used for othe rpurposes, the chemical has to be
tested for compliance.

       Bruce Hamilton