Aseptic Process Validation Approach

The validation of the aseptic manufacturing process in a holistic approach which includes validation of qualification of any and all support systems which can adversely affect the sterility of product or the quality of product.

Aseptic Process Simulations

A conventional aseptic process is among the complex drug manufacturing processes. It involves the interaction of human intervention and activity with the uncertainty of environment effects. Human interventions have the potential of depositing microbiological contamination onto a product contact surface. The gowning and gloving technique may and result in microorganisms on gown and glove surfaces. Clean room environment air can transfer particles laden with microorganisms from gowns and other surfaces to the environment. Flows of air in and around product contact surfaces and open components have no real barriers to microbial ingress. The likelihood of ingress and possible contamination is dependent on intervention position and technique in and around air flow patterns designed to keep contamination off and out of these surfaces. Isolators and barrier system interactions are complex due to mechanical and environmental effects, movements, surrounding area conditions, disruptions, ingress and egress of products and items.

The aseptic process simulation (APS) or the media fill test (MFT) is a way to provide additional assurance of process control and performance. The APS provides both a demonstration of and a challenge to the aseptic process. It is conducted in a manner close to the actual manufacturing operation as possible, substituting growth promoting media for product. If levels of contamination are inherent in the process, they might come in contact with the media and grow to the point of detection, thus providing evidence that the process may not be adequate.

The APS is part of overall process validation approach, challenging the capability of the aseptic process to produce sterile drug products. It evaluates the capabilities of the aseptic process operation by simulating the process from the point of sterilization of the bulk product to closure of the container. It can be used to assess changes made to an aseptic processing operation which might impact the sterility of the final product, identify weaknesses in aseptic processing which might contribute to the microbiological contamination of the product, and evaluate the proficiency of aseptic processing personnel and demonstrate the appropriateness of operating practices used in support of aseptic processing.

The APS is one tool for evaluating the processing steps used to manufacture a sterile product. It is part of an overall approach used to assure controlled aseptic processes. An aseptic process incorporates many systems to assure and control sterility of the materials; including:

  • product, equipment and component sterilization
  • personnel training and certification of aseptic gowning and aseptic techniques.
  • equipment and facility sanitization programs
  • environmental controls: microbial levels, differential pressure, air pattern, velocity, temperature and humidity.
  • personnel, material and equipment flow and transfer (PDA, 2009).

The APS is a way to test if an aseptic process is adequate to protect sterile product from microbiological contamination. It is also a way to uncover weakness in the process. A good risk assessment and evaluation of the process should determine areas where product is at risk of contamination. The firm can then take steps to mitigate or eliminate those risks through process or system design improvements.

Element of the APS

The APS is a simulation of those production process steps which can have an effect sterility and microbial contamination of product. Any and all process steps which can have an effect on sterility should be included in the simulation.

The APS study should not enhance or interfere with the process. The APS steps should not increase or decrease the potential for sample or filled unit contamination, except as designed in the study. Steps or conditions should not be less challenging than normal production, as that would be an insufficient challenge of the process and therefore cannot provide assurance of process control. Steps should not add elements to the process which are not present in normal production and could add potential for unit contamination, as that would make evaluation of failure and determination of cause more difficult and potentially misleading.

The APS should not be used to justify the use of a questionable or “unacceptable” practice or condition. The absence of contamination in a filled unit may be the result of random conditions and interactional effects.