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W 06: Design of Physicochemical Compatibility Studies for Sterile Injectable Products: Key Lessons from Recent Filings

Poster Presenter

      Eli Zavialov

      • Director, Regulatory CMC Dossier Development and Operations
      • Johnson & Johnson
        United States


Describe global regulatory requirements and key considerations for the design of in-use stability (compatibility) studies for sterile injectable products. Formulate and deploy an appropriate scientific and regulatory strategy for compatibility studies depending on product specifics to ensure expedient global regulatory approvals.


The presentation provides an overview of recent experience related to pharmaceutical development and regulatory approval of in-use stability (compatibility) studies in support of global marketing applications for sterile injectable products. Two detailed case studies are presented on lyophilized sterile drug products for reconstitution and dilution: one including a product that has limited solution stability, and the other including a product with a long administration (infusion) time. The presentation explores the different approaches and unique challenges associated with the specific product types and regional regulatory requirements.


For Product A (product with a limited solution stability), in-use stability studies were conducted to support 2 separate indications with different required infusion times. In-use storage conditions were proposed for immediate and delayed drug product administration. Following the initial submission of global marketing applications, the originally proposed in-use storage conditions were revised based on the feedback received from the FDA and EMA to ensure that the administered drug product complies with its specifications up to point of administration while minimizing the drug product degradation. A strategy to align the legacy global filings was developed and successfully deployed. For Product B (unpreserved product with a long administration time), in-use stability data to demonstrate acceptable chemical and physical stability for up to 30 hours and acceptable microbial stability over 60 hours was provided in the original NDA. Based on the guidance received from the FDA regarding the design of post penetration stability studies for sterile drug products, additional in-use stability studies with spiked microorganisms were conducted. These studies supported a hold time of up to 8 hours at room temperature, which was not sufficient to enable the required infusion time of 24 hours. Further studies were performed with lower starting inoculum levels and using either a bacteriostatic agent or an in-line sterilization filter. The results of the study with a bacteriostatic agent demonstrated that this approach was not feasible, as the allowable daily intake of a bacteriostatic agent was exceeded while still failing to reach the required minimal inhibitory concentration. On the other hand, microbial challenge studies with in-line filters demonstrated the effectiveness of microbial removal and provided a viable solution to ensure the control over adventitious pathogens that may be introduced during solution preparation


It is important to study the physical, chemical and microbial properties of the drug product that are susceptible to change during storage over the period of the proposed in-use shelf-life. Lyophilized sterile drug products for reconstitution and dilution may present special challenges due to limited solution stability or long required infusion times. For the case of a product with limited solution stability, degradation kinetics after reconstitution and dilution was thoroughly understood and suitable in-use storage conditions developed to ascertain that the product complies with its specifications up to the point of administration to the patient. The proposed in-use storage conditions also took into account the typical drug product preparation, handling, and transportation times from hospital pharmacy to the patient. For the case of a product with a long administration time, the risk of contamination with adventitious pathogens that may be introduced during solution preparation was addressed. Microbial spiking studies have demonstrated that the diluted drug product supported microbial growth over the proposed storage time. Thus, two risk mitigation approaches were proposed and examined: use of a bacteriostatic agent or an in-line sterilization filter. The latter approach was shown to be the commercially viable approach that was approved by the FDA.

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