This article aims to explain, in a very clear way, how the development of a process should be carried out for a vial lyophilized product in aseptic environment and how to define the workable space of design in which are achieved the critical attributes of product quality.
Reliability through QbD
At the end of 2007, the Q8 guide of the ICH (International Conference of Harmonization) already introduced us very clearly to where to focus our effort in the future of drug manufacturing processes. Specifically, it defined the following concepts that will be key for the correct understanding of the present article:
Quality Target Product Profile
Quality critical attributes
Risk analysis (Q9). To link attributes of process materials and parameters to Quality Critical Attributes
Important to keep in mind that the FDA and the EMA are increasingly reluctant to the approval of new product registrations whose manufacturing process has been developed and subsequently validated by empirical methods. The repetitiveness applied to a manufacturing process of a pharmaceutical product should not be consider robustness. It is essential to know how close or far we are from a possible failure situation.
Quality Target Product Profile
In table 1 we define quality attributes of an injectable lyophilized product in vials. Although many times it is not easy, it is essential to objectify all the attributes of quality to avoid confusion or misinterpretations.
Process materials and parameters attributes
The product temperature is a critical factor throughout the entire lyophilization process (freezing, primary drying and secondary drying), but we can not consider it as a critical process parameter since the equipment is not able to ac directly on it. To be able to increase or decrease the product temperature we must modify the chamber pressure and / or the shelves temperature. These two parameters are to be considered as critical process parameters. The greater or lesser heat transfer towards the product is the key factor that will determine all quality attributes except for sterility, which comes determined by environmental control factors (Figure 1).
1) Convection heat transmission.
2) Heat transmission by conduction.
3) Transmission of heat by radiation.
Material attributes that affect the transmission of heat are:
Geometry of the vial
Height of the filled solution
Characteristics of the dissolution
Loading system (presence of trays)
Distance between the vial and the upper shelf
Distance between the vial and the lyophilizer wall
All these characteristics are fixed, so they do not vary during the process or between processes, are part of the product characteristics and therefore should be taken into account in the lyophilization cycle development study.
Regarding the parameters these are related to the phase of the lyophilization cycle considered: during freezing step time and shelf temperature are to be set while during primary and secondary drying the parameters to adjust are time, shelf temperature and chamber pressure.
The introduction of the concepts of Quality by Design in the world of lyophilization has been key to boost the innovation and deep knowledge of the process. What a few years ago defined as art, more and more can be explain through science and more specifically through thermodynamics.
It is exciting to see everything we have advanced in the knowledge of the process thanks to innovations such as wireless sensors, the steam flow measurement system, the product analysis through microscopy, the nucleation induction during freezing, etc.
There is still a big room for innovation in the lyophilization world!