Introduction
This document provides guidance for design, operation, and commissioning or qualification of lyophilizers and the validation of lyophilization processes.
1. Definitions– the following terms apply specifically to lyophilization as used in this guidance.
Collapse Temperature – in the lyophilization of amorphous systems, that temperature below which primary drying must occur to prevent loss of product cake structure (i.e., meltback).
Degree of Supercooling – the number of degrees below the equilibrium freezing temperature where ice first starts to form.
Eutectic Temperature – for crystalline solutes, a point of a phase diagram where all phases are present and temperature and composition of the liquid phase cannot be altered without one of the phases disappearing. Primary drying must occur below this temperature to allow for complete sublimation.
2. Lyophilization Cycle Development should include consideration of the following:
- Characteristics of raw material (RM) (e.g., Mannitol);
- Product formulation and formulating procedures;
- Product characterization such as pH, phase transition temperature, and finished product quality;
- Stability of the product as a solution prior to lyophilization;
- Characterization of product freezing profile;
- Product Collapse Temperature/Eutectic Temperature and/or melting temperature;
- Degree of supercooling of product solution during freezing;
- Stability of lyophilized product processed at the critical process parameter ranges;
- Time limits for holding during freezing, primary drying, and secondary drying steps;
- Stability of lyophilized product at the limits of the finished product specifications for residual moisture;
- Sealing of product containers under vacuum or with an inert gas overlay;
- Effect of partial meltback on product performance and stability;
- Container/closure compatibility;
- Acceptable residual moisture level in finished product;
- Range of critical parameters;
- Appearance of the cake; and
- Reconstitution properties.
3. Commissioning and Qualification of Lyophilizers should include the following:
- Vacuum leak rate, maximum vacuum level, chamber pressure control, and condenser capacity are verified;
- A minimum of three temperature distribution studies on an empty chamber are conducted to confirm shelf temperature control and uniformity at three temperature ranges representing the three phases of the lyophilization cycle (i.e., freezing, primary drying, and secondary drying);
- At least one product study is conducted using simulated or actual product; and
- Media Fills are performed.
4. Microbial Retentive Filters should be integrity tested before and after use.
5. Shelf Temperature Control and Uniformity Studies should be conducted simultaneously. Documentation should include:
- Temperature uniformity of each shelf, including corners, centre, and heat transfer fluid inlet and outlet pathways;
- Placement of temperature probes;
- Maximum and minimum cooling and heating rates;
- Thermal gradient across the shelf at cooling and warming setpoints; and
- Shelf temperature control to within +/-3o C at three setpoints (e.g., cold at -25 o C, intermediate at 0 o C, and warm at 25 o C).
6. Lyophilization Qualification should include:
- Media fills simulating lyophilization processes;
- Cleaning of chamber, condenser, and trays;
- Cleaning validation of the chamber and trays and
- Sterilization validation of the chamber, condenser, and trays.
- Moisture content,
- Cake appearance, and
- Reconstitution properties.
- Chamber,
- Condenser,
- Vent filter and piping,
- Sampling ports (if any), and
- Exposed drain piping (if any).