Interactions of leachables with drug products and drug substances, focus on biologics

Extractables and Leachables (E&L) studies are not only needed/mandatory to be able, upon identification of the chemical molecules in contact with the patient through the final medicine, to toxicologically assess the safety of the drug product for the patient till the end of the shelf life. But the information gathered is also vital in view of potential adverse/unwanted reactions, more specifically the potential interaction between specific leachables and components of the medicinal product (final form including the CCS – container closure system).

?

One of most known (unwanted) interactions is likely the Eprex? case from 1998 whereby pure red cell aplasia (PRCA) in chronic kidney disease patients treated with epoetins substantially increased. This has been associated, after a in-depth investigation, to identified organic compounds leached from uncoated rubber stoppers in prefilled syringes. Since then one uses preferably coated rubber closures, e.g. fluorine coated.

Also the interaction of Tungsten (symbol: W) with protein containing drug products is well documented as this causes denaturation once the Tungsten concentration exceeds a threshold concentration. This is of concern for (prefilled) syringes as Tungsten can be residual from the production process. A lot of scientific articles exist on this item (see the one from Seidl et al. from 2012). And there’s also an ISO norm for the analytical testing of (batches of) glass syringes on the level of extractable Tungsten, namely ISO 3749 (updated in 2022). This ISO norm is an important tool in de QC testing of glass syringes when biologics are the drug product to be administered.

?

Another possible interaction of concern is the one from some metallic leachables, originating from glass vials with Polysorbate 20 or Polysorbate 80. The resulting interaction of the latter and its effects have been extensively studied a.o. by Mould et al and published in Pharmaceutical Research in 2023. An interesting read in view of the impact on biological drug products (focus on antibody formulations where a vast majority contains polysorbates).

Similar to the other cases described above, the oxidation of polysorbate can lead to the loss of the drug’s potency and to protein denaturation. The impact of parameters like pH, light exposure and peroxide content has been documented, but in this article the research team deep dives into the effect of the primary container system, with a focus on glass and polymeric vials. ?The most commonly used materials are Type I glass and (gamma irradiated) COP (cyclic olefin copolymer) vials. The former material has been investigated with 51 COE ?and 33 COE glass (difference in the expansion coefficient) which has proven to have an effect (and different impact).

Analytical techniques are RP-HPLC with UV-detection for the quantification of PS80 (Agilent 1100) and ICP-MS with collision cell gas modes, the latter technique to profile for the elemental impurities and linked them to the effect on PS80 oxidation (Agilent 7900).

The cross-over of different science domains is what always triggers me and is interesting, and in this research some empirical model is set for Total Oleic Acid (TOA), the so-called Avrami modelling.

?

There’s of course the profile in elemental impurities from the various CCS with the actual level measured. At the low ppb (μg/L) levels of for example aluminum (Al), copper (Cu) , iron (Fe) or calcium (Ca) none of these metallic species can enhance the PS80 oxidation process except for aluminum. This element is more present in glass and certainly in 51 COE type, and at higher temperatures, all logical observations, but good that they’re proven experimental. That’s what Science is all about !

On the other hand, a synergistic effect -another nice scientific effect – has been observed between Al and Fe, on top of the present catalysis of the PS80 oxidation mechanism.

?

The research indeed proves the importance of considering the type of CCS and a thorough check of the E&L profiles and their potential effect on the drug product, the latter always been slightly different in composition. So doing some homework in those upfront considerations is needed and can be achieved with the right information and knowledge.

There’s a lot of solid, scientific information out there, unfortunately there aren’t enough good platforms, overarching businesses and companies, where information is discussed, collected and used to build a kind of general knowledge and understanding, helping an entire industry forward in the benefit of the patient ultimately.

?

References

R. Mould, P.W. Sargent Jr, Y. Huang, A.L. Fields, L. Zhang, F.C. Herbert, S.L. Stewart and T. Wang; Impact of Primary Container Closure System on PS80 Oxidation and the Mechanistic Understanding; Pharm Res, 40, 1965-1976, 2023

A. Seidl, O. Hainzl, M. Richter, R. Fischer, S. B?hm, B. Deutel, M. Hartinger, J.Windisch, N. Casadevall, G. M. London andI. Macdougall; Tungsten-Induced Denaturation and Aggregation of Epoetin Alfa During Primary Packaging as a Cause of Immunogenicity; Pharm Res, 29,1454–1467, 2012

ISO 3749:2022 Glass syringes — Determination of Extractable Tungsten

#tungsten #biologics #protein #denaturation #drugpotency #polysorbate80 #PS80 #toxicology #extractables #leachables #ISO3749 #glassvials #COP #gammairradiation

Thor Rollins Audrey Turley Sarah Campbell, PhD, DABT Aryo Nikopour Shiri Hechter Aaron DeMent Dania Cortes Alpa Patel Matt Cushing Martell Winters Michelle Lee Johan Jaubin Hannes De Vos Dimitrios Kipros Deirdre Cabooter MedPharmPlast Europe Horst Koller Jochen Heinz Sona Kovackova Matthew R. Jorgensen, PhD, DABT Nicholas Christiano M.S., MBA Krista B. Matthias Onghena Jonas De Vits