Document yb269146JOBoqe872yq9oE7p2

Sector and (sub-)uses concerned Medical devices (Annex E.2.9.) -- Other coating applications / Diagnostic laboratory testing 1. Analytics - TRIFLUORO ACETIC ACID (TFA) Introduction An estimated 537 million people worldwide are affected by diabetes. According to the International Diabetes Federation, the number of chronically ill people is expected to increase significantly by another 46 percent by 2045 (1). In Germany, 9 million people suffer from diabetes, of which approx. 373,000 for type I (autoimmune disease in which the immune system is directed against the body) and 8.7 million for type II (chronic disease with progressive reduction in insulin production). With up to 560,000 new diagnostics per year (of which approximately 8,000 type I diseases) an additional 3.5 million patients are expected until 2040. The main therapy for type I diabetics is insulin (2). Therefore, to ensure a safe supply of insulin to patients, reliable quality control of the drug is a necessary, prerequisite and tests need to be carried out prior to release of the drug (3) High quality recombinant insulin requires being free of single-chain precursor, a task that depends on the selectivity and sensitivity of the monitoring process for precursor detection. The specific method developed for this purpose requires the use of the PFAS substance trifluoroacetic acid. Details TFA is used as a mobile phase additive in the reversed-phase high-performance liquid chromatography (RP-HPLC) of biological molecules, such as proteins and peptides (Insulin as a peptide hormone), because it acts as an ion-pairing reagent and equilibrates quickly so that it can be used with gradient elution. The volatility of TFA also has made it a favorite additive for LC-MS applications (4). Generally, TFA has been employed in a concentration range of 0.05-0.1% for the majority of peptide separations. Ionic mobile phase additives like TFA serve one or more of the following functions: pH control (buffering), complexation with oppositely charged ionic groups to enhance reversed phase retention (ion pairing), or suppression of adverse ionic interactions between peptides and silanol groups on the silica. Example: Effect of TFA concentration in the mobile phase of amino acid separation (5): . Substitution Of the different attempts for optimizing the LC/MS separation of proteins and peptides the one important is to reduce or avoid TFA without losing high efficiency and peak symmetry. Various tries have been made to replace TFA as an additive in the mobile phase without satisfactory results. TFA is a very strong acid and fully ionized. 0.01M TFA has a pH2, suppressing ionization of weakly acidic compounds, while for example the ecologically more favorable acetic acid with a pKa of about 5 is unsuitable for this purpose. An alternative which has been discussed, Difluoro acetic acid does not avoid the PFAS topic (6). Safe Handling - Risk Management During laboratory work, only trained employees are handling TFA under GLP/GMP conditions. The waste solvents generated during the analysis process (including TFA) are collected separately and fed closed to incineration. Incineration offers the only possibility to completely destroy TFA (7) with the pyrolysis products CO, CO2, CF2, CF2O (8). Conclusion: Without TFA for drug substance analysis, sufficient separation of the chromatography phases is no longer given, and no quality release of the drug is possible without putting the patient at risk. There should be an unrestricted exception for the analytical and laboratory area to ensure treatment of patients suffering from diabetes. 2. Elastomers for Primary Packaging Systems - Coated STOPPERS Introduction Rubber stoppers are an essential part of primary packaging as elastomeric closure system components, while distributing medicines to patients or health care facilities. Figure 1 - Stoppers and plungers Source: Aptar Primary packaging components come in intimate contact with drug products - they can affect both drug product and patient safety. Pharmaceutical rubber formulations for drug product closures are of high quality, but as formulations and as a result of vulcanization processes, they contain various reaction products, additives, stabilizers, etc., which can appear as so called "extractables and leachables". At this up to 50 impurities could occur. Especially biopharmaceutical products (like peptides, hormones, monoclonal antibodies, proteins,...) are extremely sensitive to contamination with regard to their stability (9) (10) . Due to these boundary conditions, direct interaction with the rubber surface must be avoided. Technically, this is done by shielding the stopper surface with an ETFE (ethylene tetrafluoroethylene, TeflonTM) membrane. Figure 2 X-ray tomography of a PremiumCoat stopper inserted onto a 6R ISO NBB vial. The ETFE film coating is represented in blue and does not interfere with the valve, transition or land seal area, as defined by the Parenteral Drug Association. (11) This guarantees the stability of the pharmaceutical preparation, shortens the time required for development for clinical testing (only the compatibility with the membrane has to be ensured) and thus favors the availability of new therapeutics and increases patient safety due to a known "byproduct profile". Furthermore, ETFE shows stability in sterilization processes (up to 125 C) and is characterized by low film thickness and contourability. Lessons learnt - The Eprex case The FDA requirement to deliver toxicological studies for Extractables and Leachables (E&L) of materials in contact with the product as part of the official pharmaceutical approval procedures has its origin in the "Eprex Case". The incidence of pure red cell aplasia (PRCA) in chronic kidney disease patients treated with epoetins increased substantially in 1998, was shown to be antibody mediated, and was associated predominantly with subcutaneous administration of Eprex. A technical investigation identified organic compounds leached from uncoated rubber stoppers in prefilled syringes containing polysorbate 80 as the most probable cause of the increased immunogenicity (12) (13) (14). So, a unique and standardized ETFE sealing film is an efficient protection from exposure to E&L and will avoid fatalities in patients. Consequences The withdrawal of an established and safe coating material has a negative impact on several aspects for drug safety, handling and further development: As biopharmaceutical drugs are very sensitive to impurities, drug product development will be ceased if no stable dosage form can be found. Huge increase of E&L analytics and toxicological assessment (study duration 2 years) for each drug product and each different stopper material. Thus significantly prolonging development time and market entry for patient care Elaborate stability and compatibility investigations. Patient safety will be reduced due to unnecessary exposure to impurities (from rubber) with unknown accumulation under chronic use. Conclusion For the use of barrier membranes for injection products, ETFE is an essential material which should get a permanent exemption for further use to safeguard medicinal supply. Literature 1. Bocksch, Ren. Diaetes nimmt weltweit zu. [Online] 12. 11 2021. [Zitat vom: 05. 09 2023.] https://de.statista.com/infografik/6695/anzahl-der-zuckerkranken-weltweit-nach-region/. 2. Deutsche Diabetes Gesellschaft (DDG) und diabetesDE - Deutsche Diabetes-Hilfe. Deutscher Gesundheitsbericht Diabetes 2023. 55130 Mainz : Verlag Kirchheim + Co GmbH, 2022. ISSN 1614-824X. 3. Europe, Council of. EUROPEAN PHARMACOPOEIA. Strasbourg : EDQM Council of Europe, 2023. Bd. 11.2. 2084. 4. Separation Science HPLC Solutions. Separation Science - Buffer preparation. [Online] [Zitat vom: 05. 09 2023.] https://blog.sepscience.com/liquidchromatography/hplc-solutions-12-buffer-preparation. 5. Yang Huang, Tiejie Wang, Marianne Fillet, Jacques Crommen, Zhengjin Jiang. Simultaneous determination of amino acids in different teas using supercritical fluid chromatography coupled with single quadrupole mass spectrometry. Journal of Pharmaceutical Analysis. 9, 2019, Bd. 4, S. 254-285. 6. Tipps fr hhere Empfindlichkeit in der LC-MS. 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Cordier S, Brocco B, Verger E, Clausse A. Cold Storage and Container Closure Integrity - Demonstrated Performance of ETFE-Coated Components. ONdrugDelivery. May 2023, Bd. 147, S. 6-11. 12. Villalobos, A.P., Gunturi, S.R. & Heavner, G.A. Interaction of Polysorbate 80 with Erythropoietin: A Case Study in Protein-Surfactant Interactions. Pharm Res. 2005, Bd. 22, S. 1186-1194. 13. Katia Boven, Scott Stryker, John Knight, Adrian Thomas, Marc van Regenmortel, David M. Kemeny, David Power, Jerome Rossert, Nicole Casadevall. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney International. 2005, Bd. 67, 6, S. 23462353. 14. Macdougall IC, Casadevall N, Locatelli F, Combe C, London GM, Di Paolo S, Kribben A, Fliser D, Messner H, McNeil J, Stevens P, Santoro A, De Francisco AL, Percheson P, Potamianou A, Foucher A, Fife D, Mrit V, Vercammen E. 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