Aseptic processing using isolation systems Sterile Drug Products

Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice.


Aseptic processing using isolation systems separates the external cleanroom environment from the aseptic processing line and minimizes its exposure to personnel. A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control, offers tangible advantages over traditional aseptic processing, including fewer opportunities for microbial contamination during processing. However, users should remain vigilant to potential sources of operational risk. Manufacturers should also be aware of the need to establish new procedures addressing issues unique to isolators.

A. Isolator Maintenance

1. General

Maintenance of isolator systems differs in some significant respects from the traditional, non-isolated aseptic processing operations. Although no isolator forms an absolute seal, very high integrity can be achieved in a well-designed unit. However, a leak in certain components of the system can constitute a significant breach of integrity. The integrity of gloves, half-suits, and seams should receive daily attention and be addressed by a comprehensive preventative maintenance program. Replacement frequencies should be established in written procedures that ensure parts will be changed before they breakdown or degrade. Transfer systems, gaskets, and seals are among the other parts that should be covered by the maintenance program.

2. Glove Integrity

A faulty glove or sleeve (gauntlet) assembly represents a route of contamination and a critical breach of isolator integrity. A preventative maintenance program should be established. The choice of durable glove materials, coupled with a well-justified replacement frequency, are key aspects of good manufacturing practice to be addressed. With every use, gloves should be visually evaluated for any macroscopic physical defect. Physical integrity tests should also be performed routinely. A breach in glove integrity can be of serious consequence. The monitoring and maintenance program should identify and eliminate any glove lacking integrity and minimize the possibility of placing a sterile product at risk.

Due to the potential for microbial migration through microscopic holes in gloves and the lack of a highly sensitive glove integrity test, we recommend affording attention to the sanitary quality of the inner surface of the installed glove and to integrating the use of a second pair of thin gloves.

B. Design

1. Airflow

There are two types of aseptic processing isolators: open and closed. Closed isolators employ connections with auxiliary equipment for material transfer. Open isolators have openings to the surrounding environment that are carefully engineered to segregate the inner isolator environment from the surrounding room via overpressure.

Turbulent flow can be acceptable within closed isolators, which are normally compact in size and do not house processing lines. Other aseptic processing isolators employ unidirectional airflow that sweeps over and away from exposed sterile materials, avoiding any turbulence or stagnant airflow in the area of exposed sterilized materials, product, and container closures. In most sound designs, air showers over the critical area once and then is systematically exhausted from the enclosure. The air handling system should be capable of maintaining the requisite environmental conditions within the isolator.

2. Materials of Construction isolator

As in any aseptic processing design, suitable materials should be chosen based on durability, as well as ease of cleaning and decontamination. For example, rigid wall construction incorporating stainless steel and glass materials is widely used.

3. Pressure Differential

Isolators that include an open portal should be designed to ensure complete physical separation from the external environment. A positive air pressure differential adequate to achieve this separation should be employed and supported by qualification studies. Positive air pressure differentials from the isolator to the surrounding environment have largely ranged from approximately 17.5 to 50 Pascals.[22] The appropriate minimum pressure differential established by a firm will depend on the system’s design and, when applicable, its exit port. Air balance between the isolator and other direct interfaces (e.g., dry heat tunnel) should also be qualified.

The positive pressure differential should be coupled with an appropriately designed opening to the external environment to prevent potential ingress of surrounding room air by induction. Induction can result from local turbulent flow causing air swirls or pressure waves that might push extraneous particles into the isolator. Local Class 100 (ISO 5) protection at an opening is an example of a design provision that can provide a further barrier to the external environment.

4. Clean Area Classifications

The interior of the isolator should meet Class 100 (ISO 5) standards. The classification of the environment surrounding the isolator should be based on the design of its interfaces (e.g., transfer ports), as well as the number of transfers into and out of the isolator. A Class 100,000 (ISO 8) background is commonly used based on consideration of isolator design and manufacturing situations. An aseptic processing isolator should not be located in an unclassified room.

C. Transfer of Materials/Supplies

The ability to maintain integrity of a decontaminated isolator can be affected impacted by the design of transfer ports. Various adaptations, of differing capabilities, allow for the transfer of supplies into and out of the isolator.

Multiple material transfers are generally made during the processing of a batch. Frequently, transfers are performed via direct interface with manufacturing equipment. Properly maintained and operated rapid transfer ports (RTPs) are an effective transfer mechanism for aseptic transfer of materials into and out of isolators. Some transfer ports might have significant limitations, including marginal decontaminating capability (e.g., ultraviolet) or a design that has the potential to compromise isolation by allowing ingress of air from the surrounding room. In the latter case, localized HEPA-filtered unidirectional airflow cover in the area of such a port should be implemented. Isolators often include a mousehole or other exit port through which product is discharged, opening the isolator to the outside environment. Sufficient overpressure should be supplied and monitored on a continuous basis at this location to ensure that isolation is maintained.

D. Decontamination

1. Surface Exposure

Decontamination procedures should ensure full exposure of all isolator surfaces to the chemical agent. The capability of a decontaminant to penetrate obstructed or covered surfaces is limited. For example, to facilitate contact with the decontaminant, the glove apparatus should be fully extended with glove fingers separated during the decontamination cycle. It is also important to clean the interior of the isolator per appropriate procedures to allow for a robust decontamination process.

2. Efficacy

The decontamination method should render the inner surfaces of the isolator free of viable microorganisms. Multiple available vaporized agents are suitable for achieving decontamination. Process development and validation studies should include a thorough determination of cycle capability. The characteristics of these agents generally preclude the reliable use of statistical methods (e.g., fraction negative) to determine process lethality . An appropriate, quantified Biological Indicator (BI) challenge should be placed on various materials and in many locations throughout the isolator, including difficult to reach areas. Cycles should be developed with an appropriate margin of extra kill to provide confidence in robustness of the decontamination processes. Normally, a four- to six-log reduction can be justified depending on the application. The specific BI spore titer used and the selection of BI placement sites should be justified. For example, demonstration of a four-log reduction should be sufficient for controlled, very low bioburden materials introduced into a transfer isolator, including wrapped sterile supplies that are briefly exposed to the surrounding cleanroom environment.

The uniform distribution of a defined concentration of decontaminating agent should also be evaluated as part of these studies . Chemical indicators may also be useful as a qualitative tool to show that the decontaminating agent reached a given location.

3. Frequency

The design of the interior and content of an isolator should provide for its frequent decontamination. When an isolator is used for multiple days between decontamination cycles, the frequency adopted should be justified. This frequency, established during validation studies, should be reevaluated and increased if production data indicate deterioration of the microbiological quality of the isolator environment.

A breach of isolator integrity should normally lead to a decontamination cycle. Integrity can be affected by power failures, valve failure, inadequate overpressure, holes in gloves and seams, or other leaks. Breaches of integrity should be investigated. If it is determined that the environment may have been compromised, any product potentially impacted by the breach should be rejected.

E. Filling Line Sterilization

To ensure sterility of product contact surfaces from the start of each operation, the entire path of the sterile processing stream should be sterilized. In addition, aseptic processing equipment or ancillary supplies to be used within the isolator should be chosen based on their ability to withstand steam sterilization (or equivalent method). It is expected that materials that permit heat sterilization (e.g., SIP) will be rendered sterile by such methods. Where decontamination methods are used to render certain product contact surfaces free of viable organisms, a minimum of a six-log reduction should be demonstrated using a suitable biological indicator.

F. Environmental Monitoring

An environmental monitoring program should be established that routinely ensures acceptable microbiological quality of air, surfaces, and gloves (or half-suits) as well as particle levels, within the isolator. Nutrient media should be cleaned off of surfaces following a contact plate sample. Air quality should be monitored periodically during each shift. For example, US fda recommend monitoring the exit port for particles to detect any unusual results. Media used for environmental monitoring should not be exposed to decontamination cycle residues, as recovery of microorganisms would be inhibited.

G. Personnel

Although cleanroom apparel considerations are generally reduced in an isolator operation, the contamination risk contributed by manual factors can not be overlooked. Isolation processes generally include periodic or even frequent use of one or more gloves for aseptic manipulations and handling of material transfers into and out of the isolator. One should be aware that locations on gloves, sleeves, or half suits can be among the more difficult to reach places during decontamination, and glove integrity defects might not be promptly detected. Traditional aseptic processing vigilance remains critical, with an understanding that contaminated isolator gloves can lead to product nonsterility. Accordingly, meticulous aseptic technique standards must be observed , including appropriate use of sterile tools for manipulations. gmp guidelines

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This Guidance is published by US FDA on September 2004

We also recommend our readers to visit US FDA’S website for undated guidances on sterile drug products

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