Applying Quality by Design to Lyophilization - Featuring expert insights from GSK Biologicals, Baxter Pharmaceutical Solutions, GEA Pharma Systems, and more. - BioPharm International


Applying Quality by Design to Lyophilization
Featuring expert insights from GSK Biologicals, Baxter Pharmaceutical Solutions, GEA Pharma Systems, and more.

BioPharm International
Volume 25, Issue 5, pp. 22-29

Lyophilization is often necessary for pharmaceutical products to improve stability or shelf-life. However, the process can present difficulties, particularly when scaling up from the laboratory to commercial production. We bring experts together to discuss best practices for developing a lyophilization process, including quality by design and design space.

BioPharm: What types of unique approaches and product knowledge are required when using a QbD approach to lyophilization?

Gieseler (University of Erlangen-Nuremberg): We need to find a more profound translation for experiments conducted in different scales of equipment.

Henning Gieseler (University of Erlangen-Nuremberg)
Successful freeze drying requires a sound understanding of both product and process related attributes, as well as the corresponding analytical tools used during product and process development to representatively measure them. When we look at the desired final quality characteristics of a freeze-dried product, the term 'quality' is, in the first instance, unrelated to the stability of an API, but targets other characteristics, such as cake elegancy, reconstitution time, moisture content and other parameters. A vial with a collapsed cake is routinely rejected from the batch during optical inspection, even though API stability may be perfectly acceptable from a pharmaceutical point of view. Optical inspection is one of the first tests to be performed on a freeze-dried product, not API stability.

Michael J. Pikal (University of Connecticut)
The connecting link between 'quality attributes' and 'product/process attributes' is often grounded in the physicochemical behavior of the formulation, which is a function of temperature and time. Physicochemical properties, such as the critical formulation temperature (the glass transition temperature of the freeze concentrated solute (Tg') for amorphous products or the eutectic temperature (Teu) for crystalline materials) are important parameters that must be determined prior to cycle development. Then, the goal is to control product temperature at the ice sublimation interface below this critical temperature during the cycle to avoid elevated mobility in the system and morphological changes, such as shrinkage, collapse and melt. In industry, differential scanning calorimetry (DSC) has been used for decades to assess the thermal fingerprint of a material. DSC is a powerful tool, but not perfectly representative for the real freezedrying situation of a product. A more representative procedure is the determination of the collapse temperature (Tc) by freeze-dry microscopy (FDM). The technical set-up of an FDM experiment is currently the best way to simulate freeze-drying in microscale, but still presents obstacles in data interpretation.

Bearing these critical temperatures in mind, freeze drying demands reliable and representative control of the product temperatures at the ice sublimation interface during primary drying to obtain a high-quality product. Many commercially available PAT tools (e.g., manometric temperature measurement, TDLAS and others) help during the developmental stage to determine product interface temperatures, but such tools can often not be used in a production environment. As a result, the biggest obstacle and challenge for the future when establishing a reliable QbD concept for freeze drying is to determine (relevant) critical product and process parameters that are also scalable.

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