Freeze Drying: The Experts' View - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

Freeze Drying: The Experts' View
Lyophilisation 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 lyophilisation process, including quality by design (QbD) and design space.


Pharmaceutical Technology Europe


Q. What types of unique approaches and product knowledge are required when using a QbD approach?


Diamond Sky Images/Digital Vision/Getty images
Gieseler: 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.

The connecting link between 'quality attributes' and 'product/process attributes' is often grounded in the physicochemical behaviour 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 scaleable.

Mayeresse: Lyohilisation has evolved a lot during the last twenty years. Years ago, lyophilisation development mainly relied on the skills of scientists who learned by a trial and error process. Today, analytical tools exist to assist the development of the freeze-drying process. For instance, apparatus such as a cryomicroscope enable the determination of the glass transition temperature, which is used to set up the temperature and pressure during the primary drying phase of a freeze-drying cycle. For a QbD approach, it is quite easy to define at which step each tool will apply and what will its output will be on the process.

Today, the development of a new process is more systematic, which gives developers more time to concentrate on the product's specificity.

Nail: At Baxter, the QbD approach to freeze dry cycle development and optimisation relies heavily on a process analytical technology called tunable diode laser absorption spectroscopy (TDLAS). This is a near-infrared technology that measures the instantaneous mass flow rate of water vapour from the chamber of the freeze-dryer to the condenser. We also use fairly standard methods for characterising the formulation, such as low temperature thermal analysis and freeze-dry microscopy, to determine the upper product temperature limit during primary drying. We use a graphical approach to the design space that incorporates limitations placed on the process that are based on both the characteristics of the product and the capability of the freeze-drying equipment. TDLAS facilitates measurement of the vial heat transfer coefficient as a function of the pressure, measurement of the resistance of the dried product layer to flow of water vapour, and the maximum sublimation rate supported by the equipment as a function of pressure. All of these are needed to construct the design space.


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
FDASIA was signed into law two years ago. Where has the most progress been made in implementation?
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
Reducing drug shortages
32%
Breakthrough designations
11%
Protecting the supply chain
37%
Expedited reviews of drug submissions
11%
More stakeholder involvement
11%
View Results
Jim Miller Outsourcing Outlook Jim Miller Health Systems Raise the Bar on Reimbursing New Drugs
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerThe Mainstreaming of Continuous Flow API Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler Industry Seeks Clearer Standards for Track and Trace
Siegfried Schmitt Ask the Expert Siegfried SchmittData Integrity
Sandoz Wins Biosimilar Filing Race
NIH Translational Research Partnership Yields Promising Therapy
Clusters set to benefit from improved funding climate but IP rights are even more critical
Supplier Audit Program Marks Progress
FDA, Drug Companies Struggle with Compassionate Use Requests
Source: Pharmaceutical Technology Europe,
Click here