Regulatory Aspects of Freeze-Drying
Freeze-drying or lyophilization has become an important formulation and stabilization strategy in the pharmaceutical industry for drugs, vaccines, antibodies, and other biological materials, for improving their long-term stability. For biological products whose storage in aqueous solution results in instability, freeze-drying prolongs the shelf-life by inhibiting chemical, physical, and microbiological pathways that occur in the presence of moisture. Due to the complex multi-step processes involved in lyophilization, it is crucial to ensure a robust and efficient cycle, which in turn ensures that high-quality products are consistently manufactured that meet the labelled therapeutic claim over the shelf life of the product. Most lyophilized small molecule drug products are usually very simple formulations containing the active ingredient, water, and in some cases, buffer. Even with these simple formulations, a number of post-approval manufacturing process changes occur occasionally due to their failure to consistently meet desirable target qualities such as reconstitution time, low moisture content, and stability. In most cases, the root causes for such failure are identified as poor lyophilization cycles or a lack of operator training.
An overall understanding of the lyophilization process, as well as use of optimum lyophilization process parameters, would provide the Agency with a greater level of knowledge and help with the approval process. This will also facilitate a greater understanding between the FDA and industrial sponsors on the regulatory aspects of lyophilized drug products.
This chapter provides an overview of the application of risk analysis to defining and measuring the critical parameters of lyophilization, for which a specific level of scrutiny is required, to ensure a robust and controlled process. Particular focus will be on the key steps of risk management through ICH Q9 applied to the freeze-drying process, with specific examples, as applied to the lyophilization of a model monoclonal antibody. The application of various process analytical technology (PAT) tools for monitoring and controlling the various processes, with specific examples, will also be discussed.
Key wordsQuality by design (QbD) Critical quality attributes (CQA) Process analytical technology (PAT) Regulatory requirements Freeze-drying process Optical coherence tomography (OCT)
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