Key Considerations from Genzyme for the Technology Transfer of Lyophilisation Cycles for Parenteral Drug Products

Tim McCoy, Principal Scientist at Genzyme provides insight into the work Genzyme is doing on technology transfer of lyophilisation cycles for parent drug products, as well as discussing the influence of nucleation in the scale up process. Tim will also be speaking at the 3rd Annual Lyophilisation for Biologicals Conference in Munich between the 19th and 21st of February.

Pharma IQ: Your presentation is on Key Considerations for the Technology Transfer of Lyophilisation Cycles for Parenteral Drug Products, can you give us a brief overview of the top considerations?

T. McCoy:
Considerations include developing a valid gap analysis and identifying scientific studies to bridge gaps. Its is also when you can look for opportunities for process improvements. Process understanding is key e.g. measuring Kv (vial heat transfer coefficient) and understanding pressure control as a function of sublimation conditions.

A good product understanding must be achieved if not already available as part of the initial technical transfer package. Also, keep in mind that the manufacturing process may be completely different in the receiving unit, so the behaviour of the product may be different from a stability perspective. Studies must be performed to understand the impact of new stresses on the product.

Lastly, no two freeze dryers are the same and the lyophilisation cycle performance must be understood well and fitted to the target freeze dryer upon transfer.

Pharma IQ: What challenges are you currently facing in this area?

T. McCoy:
The main challenge is to generate the data around heat and mass transfer dynamics on manufacturing freeze dryers as this project will be in direct competition with product manufacturing scheduling. Working with manufacturing and scheduling is a priority to achieve the end goals.

Pharma IQ: What are your main priorities for 2013?

T. McCoy
: The technical transfer of biological products to our site, such as building current product and process understanding by performing studies such as vial heat transfer modelling.

Pharma IQ: Can you tell us about the influence of nucleation in the scale up process – are there ways to overcome this problem?

T. McCoy:
Unless we control ice nucleation it is very difficult to claim that we apply Quality by Design (QbD) to lyophilisation cycle development and scale up. The freeze drying cycle designed in the laboratory is not representative of how it would perform in manufacturing due to (1) differences in the degree of supercooling between the laboratory and manufacturing and a (2) heat transfer differences between the freeze dryers as a direct result of freeze dryer design differences. The impact of design differences between freeze dryers on heat transfer dynamics is well understood and modelled.

Ice nucleation is a function of the particulate levels within the formulation. The lower the particulate levels, the lower the ice nucleation temperature, which results in a higher degree of supercooling and larger ice crystals. Annealing may be added to the freezing step in an attempt to achieve homogeneous ice nucleation, which has been demonstrated to be successful to a certain extent. However, to effectively control ice nucleation, techniques such ice fog and depressurization should be employed, where the  degree of supercooling can be controlled and maintained at a lower level,  making ice nucleation independent to particulate levels (or thermocouples for that matter).

It is well understood that the degree of supercooling directly influences primary drying performance. Homogeneous ice nucleation results in consistent cake morphology from vial to vial within the freeze dryer along with a more scalable freezing step, all as a result of maintaining the degree of supercooling irrespective of the manufacturing environment. Implementing ice nucleation control will simplify scale up and make the development work performed in the laboratory more relevant to the manufacturing process. Lastly, it will minimize vial to vial cake heterogeneity within and between batches at manufacturing scale.

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