♦Regarding the production control of sterile pharmaceuticals, the GMP Ministerial Order stipulates that necessary measures be taken to prevent contamination of starting materials, packaging/labeling materials, and products from contamination, etc. by microorganisms, etc..

♦PIC/S GMP Guidelines Annex 1 specifies that airflow pattern under all actual operational conditions should be evaluated to confirm that contamination risks from personnel, equipment, etc., are adequately controlled.

♦Upon reviewing the video of a smoke test conducted in the aseptic area of a freeze-dried product line, it was observed that air coming into contact with the operator who is transferring the product to the freeze dryer was flowing into the openings of partially stoppered vials. However, the potential risk of this airflow on product sterility had not been evaluated. Furthermore, smoke tests for certain processes had not been conducted.

♦When reviewing the results of environmental monitoring for the aseptic area of the production line, microorganisms suspected to be derived from operators were found. This suggested the possibility that contamination prevention measures in the aseptic area were not functioning sufficiently, indicating a defect in the Contamination Control Strategy (CCS).

♦Interviews at the manufacturing site revealed that because the production line was not used frequently, the site had lowered the priority of introducing a robust barrier system and compliance to the latest regulatory requirements and guidelines.

♦Based on the results of a newly conducted risk assessment, the contamination risk associated with interventions in the aseptic area was reduced by taking measures such as introducing dedicated jigs for product transfer, installing shielding plates etc.

♦In addition, additional smoke tests, including those for the previously omitted processes, were conducted to confirm the effectiveness of the correction measures. Furthermore, three Aseptic Process Simulations (APS) were planned before the next manufacturing run.

♦Whether the smoke test goes beyond merely “visualizing airflow” and evaluate conditions under actual operational conditions, including personnel interventions and the placement of items?

♦Whether is it confirmed that unidirectional airflow (first air) is maintained and the product is appropriately protected in the aseptic area?

♦When abnormal signals such as existence of microorganism are confirmed, whether comprehensive root cause investigation is conducted, and effective recurrence prevention measures have been taken?

✓ In smoke tests in aseptic areas, it is crucial to confirm that unidirectional airflow (first air) is maintained, and the product is protected from contamination risks under actual working conditions, including personnel interventions and the placement of goods. When evaluating test results, it is desirable to conduct an objective and multifaceted evaluation with the involvement of multiple departments, rather than relying solely on the judgment of a specific department or person in charge.

✓ In sterile pharmaceutical production, humans are the greatest source of contamination. Verification results should not be used to justify human intervention; efforts must continuously be made to reduce human intervention in production line with technological progress. If intervention operations are required, more robust contamination prevention measures are necessary.

✓ Product sterility is assured through comprehensive activities, not only sterility testing but also raw material control, operator qualification, maintenance of facilities and equipment, environmental monitoring, validation, APS, etc. Even if there are no immediate issues with the smoke test results, please comprehensively evaluate the results of environmental monitoring, APS, etc., continuously verify the effectiveness of CCS, and continue improvements toward achieving a higher level of sterility assurance.