Aseptic Processing Update

After 15 years, FDA is finally ready to update its guidance on aseptic processing. The agency released a preliminary concept paper on the subject on September 27, 2002. 

Most significantly, the concept paper, which can be read in its entirety at www.fda.gov/cder/dmpq/ aseptic-cp.pdf, offers new appendices on isolators and blow-fill-seal operations. These technologies were rarely used, if at all, when the current guidance was published in 1987.

The agency endorses the use of isolators, noting that "a well-designed positive-pressure barrier isolator, supported by adequate procedures for its maintenance, monitoring, and control, appears to offer an advantage over classical aseptic processing, including fewer opportunities for microbial con-tamination during processing." But it cautions industry not to adopt a "false sense of security" when using them.

The document calls for isolators to have a comprehensive preventive maintenance program, including written procedures for the replacement of gloves, half-suits, seams, gaskets, and seals. Gloves should be visually inspected after every use for macroscopic physical defects, and operations should be terminated if integrity breaches are found. The inner part of the installed gloves should be sanitized regularly, and operators should wear a second pair of thin gloves.

The insides of isolators should meet Class 100 standards at minimum. They should be placed in Class 10,000 or Class 100,000 cleanrooms, depending on the design of product interfaces and number of transfers performed. Unclassified rooms are unacceptable locations.

The number of material transfers should be kept to a minimum in order to lower the risk of contamination. Recommended transfer methods include direct interfaces with decon-taminating transfer isolators, dry heat depyrogenation tunnels with balanced airflow, and properly operated rapid transfer ports. If the latter allow ingress of air from the surrounding room, they should have localized HEPA-filtered laminar airflow covers. 

During decontamination, all isolator surfaces should be fully exposed to the chemical agent. Written decontamination procedures should be established and justified through process development and validation studies. Any breach of the isolator should lead to a decontamination cycle. All breaches should be investigated and any impacted products rejected.

Even though human factors are reduced when isolators are used, isolator operators should still follow metic-ulous aseptic technique.
The document commends blow-fill-seal technology for its "economies in container-closure processing and re-duced human intervention."
Blow-fill-seal machinery should be in a Class 10,000 cleanroom environment unless special design provisions justify otherwise. A well-designed blow-fill-seal system should achieve Class 100 particulate levels, and air in the critical zone (the area where sterile product or materials are exposed) should achieve Class 100 microbiological standards. 

Recommended technologies for preventing contamination of blow-fill-seal operations include barriers, pressure vacuums, microenvironments, and appropriately directed high volumes of sterile air. Smoke studies should be performed and multilocation particulate data gathered when assessing whether there is adequate particulate control in the critical zone. 

A preventive maintenance program should be established, especially for mold plates, gaskets, and other components that could affect the integrity of the boiling system.

The following aspects of blow-fill-seal operations should be validated: equipment sterilization, media fills, polymer sterilization, endotoxin removal, product-plastic compatibility, forming/sealing integrity, and unit weight variation. 

The plastic polymer material used should pass USP plastics criteria and be pharmaceutical grade, safe, and pure. 

Inspection of each unit of a batch should employ a reliable, sensitive final product examination capable of detecting a leaking unit. Significant defects due to heat or mechanical problems should be investigated in accordance with 21 CFR 211.100 and 211.192. 

The sections on classical aseptic processing contain guidance on buildings and facilities, personnel training and monitoring, components and container/closures, endotoxin control, time limitations, process validation and equipment qualification, laboratory controls, sterility testing, and batch record review.

However, more emphatically than the 1987 guidance, the new concept paper documents the agency's position that firms should employ terminal sterilization instead of aseptic processing when feasible because terminal sterilization offers fewer possibilities for contamination.