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.
Nov 01, 2008
Volume 2008 Supplement, Issue 6

Isotechniques, or techniques of adjacent volumes, are a processing method for pharmaceutical preparations containing high-potency active pharmaceutical ingredients (APIs) (e.g., cytostatics, hormones, and antibiotics) in absolute secure conditions to ensure the safety of the operator and the quality of the finished product. Manufacturing using isotechniques takes place in isolators.

Isotechniques offer certain advantages for aseptic production of injectable, high-potency drugs. In the sanitized areas of cleanrooms, the operator brings in contamination in a limited manner. A completely biodecontaminated environment exists inside the isolator, where only the drug and material for manufacturing come in direct contact with the processing system. In such operative circumstances, contamination by microbes is more limited than in cleanroom conditions because the absence of direct human intervention allows for better cleaning and complete biodecontamination of the entire working environment. Complete biodecontamination with vaporized hydrogen peroxide of the working area inside isolators allows for operation in a biodecontaminated environment. Cleanrooms, however, are exclusively sanitized and operate under conditions of controlled contamination.

A biodecontaminated environment

The automatic cycle of biodecontamination guarantees the reproducibility of the process. Manual disinfection is a time-consuming activity that may not be consistently performed and is dangerous because of the continuous exposure of operators to sanitizing agents. Biodecontaminating agents such as vaporized hydrogen peroxide achieve sterilization by the dispersion of gas. The gas can reach all surfaces exposed to its contact, even the hidden ones. Its products are oxygen and water, which are harmless. Isotechniques also exceed the onerous barrier created by the modality of clothing and microbiological control. The US Food and Drug Administration has expressed a favorable opinion for increasing the use of isotechniques for drug production in asepsis, especially for the production of high-potency APIs.

Isolators for high-potency drugs

Some aspects to consider when using isolators while processing injectable, high-potency drugs are:

  • Containment of contamination, particularly airborne contamination
  • Individual protection of personnel
  • Management of cross-contamination
  • Aseptic processing and sterility of handled material and product
  • Efficiency of biodecontamination cycles
  • Efficiency of barriers and their integrity
  • Management of the environmental impact as a result of the process (i.e., refluent, industrial waste, liquids, gas, and air).

Figure 1: Production flow for liquids in vials. (ALL FIGURES AND IMAGES ARE COURTESY OF THE AUTHOR.)
A practical demonstration of the productions of liquids or lyophilized injectables in glass vials is shown in Figure 1. The operating line is set up by several isolators partly connected in a row, where all manufacturing operations are done. These operations are: weighing of raw materials, their volatilization in tanks, transfer of the solution to the dosage systems, washing and depyrogenation of vials, filling of vials, capping (complete if liquid; partially, if liquids are to lyophilize), eventual freeze-drying, sealing, external washing, and drying of filled and sealed vials.

The process is made in a production line with isolators. The following are phases of the main production process:

  • Phase I: Preparation of the distribution circuit (distributor, needles, and tubes)
  • Phase II: Preparation of isolators (cleaning and biodecontamination)
  • Phase III: Preparation of various materials (vials, stoppers, and seals)
  • Phase IV: Preparation of the solution and its filtration.

Phase II is typically for a production process using isotechniques. Phase IV is strongly affected by the kind of API (i.e., high-potency) used in the solution preparation, and this aspect considerably changes the manipulation modalities of the API.

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