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Heike Kofler, Ph.D.

Manager, Technical Customer Support, Commercial

十二月 16, 2014

Particles in the Spotlight – Observations from Discussions at the PDA Conference on Freeze Drying Technologies 2014

To reduce and detect particulate matter is a shared responsibility between Container Closure component suppliers and the pharmaceutical industry. Keeping the patient´s safety in mind, lively discussions about particle inspection were held in the panel session at the PDA Conference on Freeze Drying Technologies.

The group focused on lyophilized presentation of drug formulations. State-of-the-art inspection techniques should be used for finished drug product that bears the risk of embedded particles or fibers within the lyophilized product, where they are hidden from detection during visual inspection procedures.

The main question focused on the feasibility and potential ways to include an opto-electronic inspection system even before the freeze drying process. At various stages, there may be sources identified to cause particulate contamination of the finished drug product. All related primary container closure systems (glass or plastic vials, elastomeric closures etc.) as well as any equipment have the potential risk to bring in particles.

Rubber closures for aseptic filling follow a manufacturing, washing and sterilization process to reduce particulate burden. Glass vials run post-washing through a heat depyrogenation tunnel in which there is a low risk that a vial may explode and shed particles into other vials. Glass containers run the risk of breakage during processing and handling, which could happen on turn tables, in the heat tunnel, on moving parts of the filling line or in the freeze dryer. Breakage can occur if the glass is under tension and mechanical stress. ETO sterilization of vials could be an alternative to the processing in the heat tunnel, but needs to be investigated to further detail.

Insight was shared that fibers will be present at the top while steel particles from the equipment accumulate at the vial base in liquid fills. The latter may be embedded in the freeze-dried drug product and could be invisible during final inspection.

Additional mechanical stress will be placed on container closure systems at the crimping stage and during labeling and application of secondary packaging material. In the case of glass containers, this requires attention to reduce glass breakage.

There is general reluctance to implement visual inspection on the liquid fill before freeze drying because the vials are spun, which causes the product to shift upwards on the inner glass walls. This may compromise the freeze drying performance and appearance of the lyophilized drug product. A suggestion was made to use vials from the Media-Fill for comparative particle inspection since these will not run through the freeze-drying cycle.

Finally, there was agreement on one important fact: finding the root cause analysis for particles is particularly complex.

Reference and acknowledgements to the participants and organizers of the PDA Conference Freeze Drying Technologies held in Brussels Belgium on 16th and 17th September 2014

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