Management of cross-contamination
Processing schemes help to individualize and graphically identify the main areas of risk for cross-contamination and the related
precautions that need to be taken. Adopting dedicated components is the principal precaution needed to avoid cross-contamination.
During solution preparation, gloves, containers, equipment for pouring, transfer tubes, and filters are dedicated to the product,
which limits common use to only the tanks. This dedication reduces to a minimum the cleaning-validation studies that show
the absence of cross-contamination between different products. The use of disposable tanks completely eliminates the risk
of cross-contamination, which allows related studies to be avoided.
During the repartition phase of the solution, gloves, transfer tubes, distributors, connections, filters and needles are completely
dedicated to the product. The adoption of push systems for the liquids such as peristaltic pumps with harmless gas or with
pressure through harmless gas mitigates the risk of cross-contamination in all production steps where these push systems are
used (e.g., from tank to tank or from tank to needles).
During post-lyophilization, cross-contamination has to be evaluated by studies that verify the efficiency of automatic processing
of cleaning in place.
Management of aseptic processing
Aseptic processing and sterility assurance is essential when producing injectable drugs with isolators. This process is connected
with the efficiency of the biodecontamination cycles of isolators and barriers and their integrity. The risky points for
the sterility assurance are as follows:
- Sterilization of material in contact with solution to fill
- Sterilization (i.e., biodecontamination) of areas with Class ISO 5, degree 100 preservation of aseptic conditions and integrity
of the interested areas
- All manufacturing phases where the possibility of contact between sterilized material and classified areas of Class ISO 8,
degree 100,000 exists.
The precautions needed to guarantee against these risks in aseptic processing are detailed below.
Sterilization of material in contact with the solution to fill
. All materials in contact are sterilized with clean steam and protected with adequate wrappings. At the end of the biocontamination
process, it must be ensured that the concentration of the oxidant agent should be less than 1 ppm in the environment and the
same environment (under the isolators) needs to be maintained for the entire duration of the production and in overpressure
with respect to the surrounding area. The solution to fill is filtered at 0.2 µm, collected, and transferred to sterile surfaces.
Biodecontamination of areas with degree 100 maintenance of aseptic conditions and integrity of interested areas
. Isolators are comparable to a classified degree 100 area with the difference of having smaller volumes liable to total
biodecontamination with vaporized hydrogen peroxide. At the end of the biodecontamination process, the concentration of the
oxidant agents should be less than 1 ppm in the environment, and the same environment (under the isolators) needs to be maintained
for the entire duration of the production and in overpressure with respect to the surrounding area. The preliminary cleaning
made inside the isolators serves not only to remove residuals but also controls the microbic contamination of the environment
before biodecontamination. The framework of the isolators is essentially made of steel and windows of glass. The only critical
point for the maintenance of the integrity is represented by the gloves used to operate inside the box. Therefore, the main
control is verifying the integrity of the gloves before and after their use. The sterility of the freeze-dryer is granted
through automatic sterilization cycles in place and through the running of the structural integrity test for the chamber made
by vacuum done at the end of each cycle.