Manufacturing High-Potency Drugs Using Isolators - Pharmaceutical Technology

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Manufacturing High-Potency Drugs Using Isolators
The author discusses the key issues to consider when using isolators such as containment, protection of personnel, the efficiency of biodecontamination cycles, sterility assurance levels, barriers and their integrity, and environmental impact.


Pharmaceutical Technology


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 m, 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.


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