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Successful Lyophilization Development and Scale-Up

Igor Nikoulin, Senior Director, Product Development and Manufacturing

Are you developing a new injectable product and encountering stability issues and need to consider lyophilization?

Everyone has an intrinsic expectation for safe and stable injectable drug products. This requires injectable products  to be developed and produced to standards of quality, purity, sterility, and stability that are uncompromising. Our state-of-the-art fill-finish line and lyophilization platform can help ensure your product will meet the most exacting quality standards and provide the shelf-life you need.

Freeze-drying cycle development

Freeze drying (lyophilization) is a means of stabilizing a product and extending its shelf life. It is frequently used in the pharmaceutical industry for small molecules and biologics. The freeze-drying process has several steps, each requiring careful optimization to maintain a product’s quality and function after lyophilization. Successful freeze-drying requires a balance of several factors, as follows.

  1. Optimization of the formulation by careful selection of cryo/lyo-protectants, buffers, excipients to inhibit the crystallization process or influence the polymorphic form, and/or bulking agents when the product is at a low concentration.
  2. Determination of thermal and physical characteristics such as the glass transition temperature and/or the collapse temperature of the product.
  3. Optimization of primary and secondary drying – temperature and pressure can be critical for biologics.
  4. Careful selection of the condenser temperature.
  5. Selection of the temperature probes to monitor the product temperature
  6. Careful consideration of shelf and product temperature during cycle development and process scale up.

Scale-up and controlled nucleation technology

Control and characterization of the degree of super-cooling are critical for addressing the biggest freeze-drying scale-up problem. Nucleation temperature is the temperature at which freezing, or ice crystal formation, begins to take place. The degree of super-cooling can have a dramatic impact on drying behavior.

Controlled nucleation technology allows nucleation at a warmer temperature. Numerous studies have demonstrated that even the slightest increase in the nucleation temperature results in a significant reduction in the primary drying time, improved cake appearance, cake morphology, vial-to-vial homogeneity, and reduced reconstitution times. Thus, controlled nucleation is rapidly becoming an important step in the development of the freeze-dry cycle and scaling up the manufacturing process. It has shown numerous benefits that can be translated into significant quality improvements and cost savings at the production scale level.

Our Galaxy S50 lyophilizer is equipped with ControLyo™ Technology, a novel, patented approach, to uniformly and rapidly induce nucleation within the freeze-dryer via pressurization and depressurization.

The multiple benefits include, but are not limited to, an increase in cake pore size and subsequent reduction in dry-layer resistance, drying time optimization, faster primary drying, improved cake appearance, and reduced reconstitution times. This technology also provides a technological advantage for the processing of biologics via reduction of freezing stress, protein aggregation, and the stability of biological samples.

Scaling up,  Clean-in-Place (CIP), and Steam-in-Place (SIP)

There is no controversy over the need for sterilization and cleaning validation for any lyophilizer that will be used in the manufacture of a sterile drug. A lyophilizer properly set up and qualified for sterilization and cleaning in the manufacture of sterile regulated products is critical. Once initial development is complete, it’s time to scale up and provide materials for clinical use.  Our Galaxy S50 lyophilizer is equipped with validated CIP and SIP systems to protect your sterile product.

Societal offers a combination of lyophilization knowledge, capabilities, and real-world experience – a prerequisite for the successful development and manufacturing of lyophilized injectable products to support pre-clinical and clinical phases. Contact us to learn how we can help develop your next injectable drug product.