Those sterile dosage forms that are stable only for a short time in solution are frequently marketed in lyophilized presentations (see Figure 3.3).
The process is more complicated than standard vial filling, although it may involve many items of common equipment. Vials are aseptically filled in the normal way, but the closures (which are of a special design) are not fully inserted.
The filled, partially stoppered vials are "trayed," taken and loaded into a lyophilizer. The traying and transfer of the vials from the filling machine to the lyophilizer may be done manually or automatically (e.g., by robotics and automatic goods vehicles). Irrespective of the means, the contents of the vials are vulnerable to contamination while they are only partially stoppered.
Within the lyophilizer the liquid in the vial is frozen and a vacuum drawn. The water from the solid (frozen) phase sublimes directly to vapour, and the dosage form dehydrates. At the end of the cycle the vacuum is broken and the closures are automatically rammed home. The main vulnerability of the process to microbiological contamination is clearly at the point where the vacuum is broken and air enters the lyophilizer and the vials. Replacement air must be filtered sterile, but other undiscovered means of air contamination from leaks, bypasses, etc. cannot be discounted.
What should and what should not be simulated?
1. The aseptic filling process should be simulated exactly as any other vial-filling process. However, since the closures and the vials may differ, attention should be given to simulating any activities that are peculiar to filling lyophilized vials as distinct from liquid-filled vials. There may be a greater frequency of intrusion to free blocked closure chutes, or to remove vials that have fallen over. Any such difference will be unique to the particular process and have to be determined empirically.
2. The traying and transfer process should be simulated exactly.
3. The lyophilization process itself must not be simulated exactly.
• The freezing of vials and the formation of ice crystals is inimical to microorganisms. Those who argue that lyophilization is one of the most frequently used methods of preserving microorganisms and is therefore not inimical, have clearly never experienced the difficulties that microbiologists endure and overcome to ensure viability when using lyophilization for preservation purposes. Freezing should not be simulated: 24 of 26 manufacturers using lyophilization who responded to the PDA's 1996 survey of aseptic manufacture claimed not to freeze their media fill vials (PDA, 1996). If there is danger of unfrozen media foaming over under vacuum and thus contaminating the lyophilizer, it may be necessary to double the size of the media fill. Simulate all of the risks up to and including loading of the freeze dryer in one-half of the media fill that is not frozen, and then simulate the subsequent risks with the rest of the filled vials that are passed through the complete process including freezing.
• A complete vacuum as specified for the lyophilization process should not be drawn. In addition to the technical difficulties of foaming, which would happen if a complete vacuum were to be drawn over the liquid rather than solid-phase dosage form, consideration should be given to any fluid loss from the media and its effect on the viability of microorganisms and the ability of the media to support microbial growth. These are two separate issues. After some concentration the media may still be able to support the growth of microorganisms, but injured microorganisms may have died as concentration took place. Typically, a partial vacuum of say 20 to 28 inches Hg is drawn, held for about two hours and "broken." Conscientious simulators of worst-case conditions may repeat this process although it is not typical of routine practices.
Some companies perform complete simulation of the lyophilization process from filling, through transfer, to lyophilization. Others may split the process into three simulations to help provide a clearer focus on what might have gone wrong if contaminated units result from the media fill. The decision as to which approach to take or how to develop a responsible combination of the two approaches is a matter of judgement. A balance has to be struck between regulatory pressure to simulate the process as closely as possible, and the need (also pursued rigorously by regulatory inspectors) to diagnose the source of contamination accurately enough to implement satisfactory corrective or preventive actions.
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