Replacing the Emulsion for Bake-on Siliconization of Containers-Comparison of Emulsion Stability and Container Performance in the Context of Protein Formulations.

Pre-filled syringes have simplified parenteral administration of protein drugs. To ensure an easy and consistent movement of the plunger, the inner glass container surface is typically siliconized. For bake-on siliconization, emulsions are sprayed on and heat treated. Due to the European Union regulation REACh (Regulation concerning theRegistration,Evaluation,Authorisation and Restriction ofChemicals) the use of certain emulsion components, partially constituting the gold standard LiveoTM 365 35% Dimethicone NF Emulsion (LiveoTM 365), becomes restricted and LiveoTM 366 35% Dimethicone NF Emulsion (LiveoTM 366) has been introduced as an alternative. This change may affect the handling properties as well as the silicone layer formed. The purpose of these studies was to identify any differences that may influence the stability and safety of the final drug/device combination product to enable the use of the new emulsion. We compared silicone emulsions LiveoTM 365 and LiveoTM 366 and dilutions focusing on 1) their general physical stability, 2) the thermal degradation process of the emulsions and their components, and 3) the resulting silicone layer concerning chemistry, morphology, and functionality. The results were linked to the assessment of the final product regarding particle formation and short-term stability. A comparison of the emulsions LiveoTM 365 and LiveoTM 366 for bake-on siliconization is presented to support the transition of the latter as it becomes mandatory with REACh. Our studies show that the two emulsions do not significantly differ with respect to handling and stability, the resultant silicone layer characteristics as well as its functionality. We conclude that the transition to the new emulsion will not significantly impact the final product or the layer performance upon storage and with respect to particle formation.

Replacing the emulsion for bake-on siliconization of containers - comparison of emulsion stability and container performance in the context of protein formulations.

Pre-filled syringes have simplified parenteral administration of protein drugs. To ensure an easy and consistent movement of the plunger, the inner glass container surface is typically siliconized. For bake-on siliconization emulsions are sprayed on and heat treated. Due to the European Union regulation REACh (Regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals) the use of certain emulsion components, partially constituting the gold standard Liveo™ 365 35% Dimethicone NF Emulsion (Liveo™ 365), becomes restricted and Liveo™ 366 35% Dimethicone NF Emulsion (Liveo™ 366) has been introduced as an alternative. This change may affect the handling properties as well as the silicone layer formed. The purpose of these studies was to identify any differences that may influence the stability and safety of the final drug/device combination product to enable the use of the new emulsion. We compared silicone emulsions Liveo™ 365 and Liveo™ 366 and dilutions focusing on I) their general physical stability, II) the thermal degradation process of the emulsions and their components, and III) the resulting silicone layer concerning chemistry, morphology, and functionality. The results were linked to the assessment of the final product regarding particle formation and long-term stability. A comparison of the emulsions Liveo™ 365 and Liveo™ 366 for bake-on siliconization is presented to support the transition of the latter as it becomes mandatory with REACh. Our studies show that the two emulsions do not significantly differ with respect to handling and stability, the resultant silicone layer characteristics as well as its functionality. We conclude that the transition to the new emulsion will not significantly impact the final product or the layer performance upon storage and with respect to particle formation.

Container Closure Integrity Testing-Practical Aspects and Approaches in the Pharmaceutical Industry.

The assurance of sterility of a parenteral drug product, prior to any human use, is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of product shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP <1207> aims to provide extensive and detailed guidance for CCI assessments for sterile products. However, practical questions and considerations are yet to be addressed by the pharmaceutical industry. These may include: (1) choice of method, for example whether a deterministic CCI method (e.g., helium leak) is preferable over the probabilistic CCI method (e.g., microbial ingress), (2) the type of primary packaging (e.g., vial, syringe, device), (3) dosage form (e.g., liquid versus lyophilisate), (4) suitable acceptance criteria, (5) appropriate sample size, (6) the most appropriate way to introduce artificial leaks into the CCS, (7) ensuring suitable assurance of CCI during drug product manufacturing, and (8) evaluating CCI under intended shipment and storage conditions (e.g., in the frozen state).A group of European industry peers have met to discuss these and other related questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).LAY ABSTRACT: The assurance of sterility of a parenteral drug product prior to any human use is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP <1207> aims to provide extensive and detailed guidance for CCI assessments for sterile products. However, practical questions and considerations are yet to be addressed by the pharmaceutical industry.A group of European industry peers have met to discuss these and other related questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).