Is an authentic standard needed in an analytical method (in E&L testing)?

An open question, applicable in many more domains where analytical chemistry is at play.

In most cases I would say “yes”, as most people working in the analytical world of chemistry and methodologies will. However, I think it’s important to always start with the intended use of the method. This is the first and the key question prior to starting any method development or validation work in the laboratory.

And for most applications and analytical laboratories the answer will be “yes” to the use and availability of an authentic standard to assess e.g. specificity and accuracy & precision (parameters in a validated method, e.g. according ICH Q2 (R2)).

However for some objectives ?it’s possible to develop a method suited for the intended use without having the authentic standard or having all of them.

An illustration by means of some hypothetical examples with Irgafos? 168 (I168) and its oxidation product Irgafos 168 oxide (I168 ox). The latter is the (intended) reaction product of Irgafos 168 which is a (secondary) antioxidant polymer additive, widely used in polymers and part of the monographs for testing the quality of the polymers used for pharmaceutical packaging [1]. In many cases and outcomes of ?Extractables and Leachables studies, the oxidation product (I168 ox) is being more detected (and quantified) than the original added form (I168). ?

(also a nice example of Intentionally added and Non-Intentionally added substances, NIAS, and their screening)

?

Let’s start by agreeing what is meant with the terminology “authentic standard” in the context of an analytical method: an individual standard with an acceptable purity to perform quantitative studies (e.g. > 97 % purity on a Certificate of Analysis) and with a CoA available stating the identity and the purity of the “pure” compound. (other descriptions and criteria are possible)

For Irgafos? 168 (a BASF commercial name and product [2]) it’s straightforward for a (contract) laboratory to purchase sufficient amounts of this product in a pure form with CoA. For the oxidized form one had to synthetize it for many years themselves whereby the oxidation was luckily quite easy, bench top possible and even described in literature. These days, it’s possible to purchase the oxidized product commercially as well.

?

For example, let’s consider a Leachables study of a drug product in contact with a container constructed with a polymer wherein this additive (I168) is one of the key additives and where the Extractables study revealed these compounds should be followed up. The intended use could be to quantify in the actual drug product during the shelf life both the Irgafos? 168 and its oxidized form (for the chemists: oxidation occurs on the central phosphor atom). In this case authentic standards are needed and the search for the best analytical technique (e.g. LC/MS or LC/MS/MS) in combination with the appropriate sample preparation, potential internal standards, predefined acceptance criteria for the method validation plan, etcetera … can be initiated and the fun work starts !

?

But let’s take another hypothetical example: in an early stage of material selection for a pharmaceutical container, one’s evaluating a number of suppliers for e.g. a polyolefine in view of their respective Extractables profile. Hereby it’s assumed all the suppliers and grades considered are pharmacopeia compliant [1] as this is the minimum requirement for polymers for these type of containers. An additional variable could be the fact that the pharmaceutical container might be sterilized, thus potentially leading to more oxidation products than in the normal conditions and shelf life.

There’s no need for a fully quantitative, validated method for the main extractables as this would be an overkill (and way too expensive) in view of the intended use, namely making a selection based on some actual data.

A possibility for the assessment of experimental data to make this decision on the material supplier (and grade) would be to analyze the total sum of Irgafos? 168 and irgafos 168 oxide after a straightforward extraction procedure with an organic solvent, ready to go on the analytical instrument after the addition of an internal standard for the injection (ISI). An option could be to develop a method based on the known UV-detectability for both species, sum up their peak area and construct a calibration curve for Irgafos? 168, easily available as a commercial standard.

With this approach,(a high volume of) samples can be easily obtained for multiple materials and treatments, measured on a HPLC/UV equipment (no need for the more expensive MS systems) and data can be obtained to assess the quality of the materials, suppliers and grades investigated.

Fast, relative inexpensive, use of standard equipment and easy in the setup and the operation … and most importantly, suited for the intended use!

?

The fact that one doesn’t need the standard for the oxidized form in this approach doesn’t mean the peak area, assigned to be the one for the oxidized form as part of the summed peak area, shouldn’t be the right one (specificity has to be fulfilled of course).

?

Another example and quite analogous could be another polymer additive, namely Irgafos? 126, a so-called stabilizer [3].?And again the oxidized form exists as described in literature, but as this polymer additive is rarely used and in lower concentrations anyway, it’s hardly ever an Extractable. Hence it rarely will be part of a method to be developed, but if this would be the case, the oxidized form should be synthetized. (note for the chemists ??: even the double oxidized form of Irgafos? 126 exists)

?

Side note:

In the screening for E&L compounds in Medical Device chemical characterization studies (based on ISO 10993), there’s been a lot of movement recently in the approach on the (semi)quantification of the detected organic compounds, e.g. guidelines and drafts from FDA and ISO committees. Especially the use of surrogates instead of all authentic standards (as the latter is impossible in the large universe of E&L compounds), is another example of methods where not always authentic standards are needed or even available and other approaches can exist.

?

References

[1] Pharmacopeia Testing on polymeric materials used for pharmaceutical packaging (and containers)

EP 3.1; 3.2 and 3.3 series

USP <661.1> and <661.2>

?

[2] Irgafos? 168 : a solid hydrolytically stable phosphite with secondary antioxidant benefits (BASF website)

[3] Irgafos? 126 : a phosphite processing stabilizer designed to prevent polymer discoloration and provide high performance at low concentration levels. (BASF website)

?

LinkedIn article on specificity in method validation

?

All comments and questions are welcome, that’s how knowledge and science grows!

www.dyfrnd.be

#authenticstandard #methodvalidation #irgafos126 #irgafos 168 #compendialtesting #polymeradditive #pharmapackaging #sterilization #extractables #leachables #ISO10993 #medicaldevice #surrogates

James Mullis James Stern Aryo Nikopour Emily Brown Rick Reiley Jason Creasey Jesper Laursen Lilla Mezriczky MedPharmPlast Europe Mike Freudenstein Anja Gottschalk Jo Bell Christian Meusinger Christian Pommereau Béatrice GRAND DEMARS David Weil Matthias Onghena Jonas De Vits Carola Damen Michelle Lee