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I've always wondered, what is the meaning of the following terms on a certificate of analysis:

  • "Heavy Metals"
  • "Heavy Metals (as Pb)"

What exactly is comprised in "heavy metals", "heavy metals (as Pb)" and what is excluded from each? What is the difference between the two variants? I tried to find a clear standard describing this to no avail.

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    $\begingroup$ To someone who studied chemistry 60 years ago this is not terribly ambiguous -- "heavy metals" are metals that are heavy. Lead, mercury, bismuth, and cadmium are prime examples, and a number of radioactive elements (such as uranium) are also considered "heavy". While some of the (lighter) heavy metals -- iron, cobolt, and zinc, eg -- are important nutrients, many (like lead) are toxic to humans. But note that the precise criteria vary, depending on the reason for the classification, so the term has apparently lost favor. $\endgroup$ – Hot Licks Nov 28 '20 at 22:22
  • $\begingroup$ Related: chemistry.stackexchange.com/questions/65495/… $\endgroup$ – Nilay Ghosh Nov 29 '20 at 2:40
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You are right heavy metals (as Pb) is a vague term. It is being discouraged and individual analysis should be reported. When someone says "I tried to find a clear standard describing this to no avail", it is a good illustration that not all information is on the webpages. It is worthwhile to search books :-)

I used to think this was an old-school analytical terminology and it turns out to be correct because it is based on classical methods. From the Food Chemicals Codex (ISBN 0-309-08866-6), which is a 1000 paged book, has the following information. Later they describe the tests as well.

Heavy Metals (as Pb)

This test is designed to limit the content of common metallic impurities colored by sulfide ion (Ag, As, Bi, Cd, Cu, Hg, Pb, Sb, Sn) by comparing the color with a standard containing lead (Pb) ion under the specified test conditions. It demonstrates that the test substance is not grossly contaminated by such heavy metals, and within the precision of the test, that it does not exceed the Heavy Metals limit given as determined by concomitant visual comparison with a control solution. In the specified pH range, the optimum concentration of lead (Pb) ion for matching purposes by this method is 20 micrograms in 50 mL of solution. The most common limitation of the Heavy Metals Test is that the color the sulfide ion produces in the Sample Solution depends on the metals present and may not match the color in the Lead Solution used for matching purposes. Lead sulfide is brown, as are Ag, Bi, Cu, Hg, and Sn sulfides. While it is possible that ions not mentioned here may also yield nonmatching colors, among the nine common metallic impurities listed above, the sulfides with different colors are those of As and Cd, which are yellow, and that of Sb, which is orange.

If a yellow or orange color is observed, the following action is indicated: Because this monograph does not include an arsenic requirement, As should be determined. Any As found should not exceed 3 mg/kg. If these criteria are met, Cd may be a contributor to the yellow color, so the Cd content should be determined. If an orange color is observed, the Sb content should be determined. These additional tests are in accord with the section on Trace Impurities in the General Provisions of this book, as follows: ‘‘if other possible impurities may be present, additional tests may be required, and should be applied, as necessary, by the manufacturer, vendor, or user to demonstrate that the substance is suitable for its intended application.’’

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  • $\begingroup$ This is good information regarding the "Heavy Metals (as Pb)" variant. Did you find a standard for the more simple "Heavy Metals" variant? Thanks a lot for your contribution! $\endgroup$ – Hans Nov 27 '20 at 17:09
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    $\begingroup$ Heavy metals means heavy metal (as used in typical sense) and it is individualized if it is written on a CoA. The manufacturer has to specify which heavy metal they are talking about. Heavy metals as Pb has a specific meaning as stated above and this term is being discouraged. $\endgroup$ – M. Farooq Nov 27 '20 at 17:28
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    $\begingroup$ "The Committee on Food Chemicals Codex notes the importance of providing limits for individual heavy metals as required by the source and composition of individual food additives. Thus, it has decided to remove from most monographs the general heavy metals (as lead) limits and tests and, based on the current level and availability of scientific information and on the policy stated below, to replace them with limits and tests for specific heavy metals such as lead, cadmium, and mercury as may be relevant to each substance" $\endgroup$ – M. Farooq Nov 27 '20 at 21:47
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    $\begingroup$ Yes. They should adopt this recommended practice. $\endgroup$ – M. Farooq Nov 27 '20 at 21:51
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    $\begingroup$ Thank you M. Farooq for taking the time to provide this information. $\endgroup$ – Hans Nov 27 '20 at 22:56
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In addition to @M.Farooq answer on the food sector, if you read heavy metals as Pb in a pharmaceutical environment, it stems from a method of the United States Pharmacopoeia, active until 2018 (same for the European, Japanese and British Pharmacopoeia as well as others). Up until then, it was normal to analyse heavy metals as a sum parameter for many drug products. The analysis was a limit test against a lead nitrate standard, where you compare the colour. From the USP chapter 231 of USP 39-NF 34 valid until 1. January 2018 :

This test is provided to demonstrate that the content of metallic impurities that are coloured by sulphide ion, under the specified test conditions, does not exceed the Heavy metals limit specified in the individual monograph in percentage (by weight) of lead in the test substance, as determined by concomitant visual comparison with a control prepared from a Standard Lead Solution. [NOTE—Substances that typically will respond to this test are lead, mercury, bismuth, arsenic antimony, tin, cadmium, silver, copper, and molybdenum.]

In addition for a lot of pharmaceutical products, special analysis for metals used in the manufacturing process were described in their monographs, such as limits of Arsenic, Iron, Lead and others.

Here is an article and a graph of the sensitivy of this method, which was quite bad.

It was a worldwide act and discussion, until finally in 2018 the International Council for Harmonisation (ICH) guidance for industry Q3D Elemental Impurities(ICH Q3D) was set in place and adopted by the regional pharmacopoeias, see FDA USP .

For the European part, here is a short "historic overview" from the European Agency.

Elemental impurities in the Ph. Eur.

The Stone age : from genesis to 2008

  • use of non specific wet chemical test for « heavy metals »
  • limit to 10 or 20 ppm > (with reference to lead)

The Bronze age : from 2008 to 2013

  • EMA GL on the specification limits for residues of metal catalysts or metal reagents

The Golden age : starting 2013

  • CHMP decision to delay the application of the EMA guideline to existing marketed products discussions on the implementation of ICH Q3D guideline

Then the chapter <231> was deleted form the USP and the chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures were released.

Now, elemental impurities are analysed by ICP or AAS on an risk based approach, mostly by studying, which elements are used in the manufacturing process, as part of the packaging, colouring etc and can leach into the drug, and then analysing the content.

So, in the pharmaceutical industry, heavy metals as Pb was a specific method for the analysis of heavy metals via colour comparison test. Until 2018, pharmaceutical products could be released with a Heav metal test based on a 1800 or 1900 visual colour comaprison test which excluded a lot of metals. Heavy metals "without Pb" did exist informal as a short version, for metals screenings and to talk about outdated methods.

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  • $\begingroup$ Thanks for providing the USP perspective. Could you clarify what is "anium hydroxide" in the first quoted paragraph. Is it ammonium hydroxide? $\endgroup$ – M. Farooq Nov 28 '20 at 21:37
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    $\begingroup$ @M.Farooq Copy past error. I only found a pdf online, with 2 columns and it copied both in a mix up. It`s deleted. $\endgroup$ – Julian Nov 28 '20 at 22:15
  • $\begingroup$ Thank you Julian!! $\endgroup$ – Hans Nov 29 '20 at 21:24

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