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


Pros and cons of aseptic techniques

Particular attention should be given to the different aseptic techniques used in manufacturing high-potency drugs. Containment and guarantee of sterility constitute the principal technical elements in evaluating isotechniques. Isotechniques offer the possibility of working with solvent products and inflammables and to render the working place inert.

Economic considerations. Taking into account economic considerations, traditional cleanrooms require lower investment than isolators, but cleanrooms do not guarantee the same sterility assurance level as the isolators. Cleanrooms are especially tied to extensive monitoring of microbiological contamination and particles, the dressing and its control, the extended surfaces to condition, the extensive use of cleaning agents, and the disinfection of the environment.


Figure 3: Comparison of cleanrooms, restricted access barrier systems, and isolators. (ALL FIGURES AND IMAGES ARE COURTESY OF THE AUTHOR.)
Although isotechniques require high installation costs, they guarantee elevated asepsis, a higher level of containment, and lower operating costs. Figure 3 compares the different features of traditional cleanrooms, restricted access barrier systems, and isolators.

Regulatory considerations. The opinions expressed by the US Food and Drug Administration and the European Medicines Agency regarding isolators have an important role in the above comparison of isolators and cleanrooms (1–7). FDA mentions isolators 55 times in its latest guideline of manufacturing in asepsis (1). This guideline (1) states:

A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and controls, offers tangible advantages over traditional aseptic processing, including fewer opportunities for microbial contamination during processing.

Moreover, FDA acknowledges removal of operators in critical areas may have the effect of increasing the asepsis conditions. It states in the guidance (1):

In contrast, a process conducted in an isolator ... can have a low risk of contamination because of the lack of direct human intervention and can be simulated with a lower number of units as a proportion of the overall operation.

Richard Friedman, director of the Division of Manufacturing and Product Quality of the Office of Compliance at FDA's Center for Drug Evaluation, recently affirmed that he would not use cleanrooms for a new pharmaceutical facility. This position is in line with the positive trend of using isolators, especially for manufacturing high-active drugs.

The incentive of using innovative technologies when producing drugs, in this case isolators, is consistent with the philosophy expressed by FDA in its report, Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach (2).

EMEA is less explicit than FDA in expressing its opinion on the most appropriate technology of aseptic production, especially of high-potency drugs. FDA was the first regulatory authority identifying isolators in its guidance in 2004 (1).

There are more isotechniques used in Europe than in the United States. The growing number of pharmaceutical facilities using isolator technology approved by EMEA in Europe seems to indicate a favorable point of view of the European regulatory authorities to isolator technology.

A trend analysis shows an increasing number of facilities using isolator technology. In 1998, 84 facilities provided aseptic filling in isolators. This number increased to 174 facilities in 2000, 201 in 2002, and to 258 facilities in 2004 (3).

The growth in the number of facilities offering aseptic processing is related to the growth in high-potency drugs. In 1995, only 5% of APIs were regarded as high-potency, compared with 50% in 2005. There are also higher numbers of high-potency pharmaceuticals coming off patent between 2010 and 2011. Also, there is an increase of high active principles as a result of reduction in dosages.


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