ORANGE LETTER
Author:
PMDA Observed Regulatory Attention/Notification of GMP Elements LETTER
Issue: June 2023
Title: Environment monitoring in the aseptic processing area
Source: https://www.pmda.go.jp/files/000252875.pdf
Related GMP Ministerial Ordinance Clause: No.1 Article 24
1. Case
Contamination risks was underestimated.
2. Background
● It is stipulated in GMP ministerial ordinance that the cleanliness of the production environment for sterile pharmaceuticals should be set and managed appropriately according to the type, dosage form, characteristics, manufacturing process, and work content of the product to be manufactured.
● At the factory, filling process of vial formulation using filtration sterilization was carried out in an open clean booth.
(Grade A (Class 100, equivalent to ISO 5)).
(Grade A (Class 100, equivalent to ISO 5)).
● Settling microbes, microbe attaching to surfaces of equipment and operators were tested at multiple points and evaluated by averaging the test results of all the test points.
The control limit for microorganisms in Grade A was set as 'The average value of all the sampling points is less than 1 CFU for all the test items'.
The control limit for microorganisms in Grade A was set as 'The average value of all the sampling points is less than 1 CFU for all the test items'.
3. Observations
● Although microorganisms were detected at several monitoring points under Grade A, they were concluded as within the control limit and there was no cause investigation and corrective action.
4. Problems/Risks
● If microorganisms have been detected in high-risk areas, such as lines where vials pass before stoppering, the products may be contaminated by the microorganism and there is a risk the sterility may not assured.
● Even though there were some problems with the qualification of equipment and operators, the cause has not been identified and appropriate corrective and preventive actions haven' t been taken. However, production was continued under these conditions with high contamination risk.
5. Check Points
● Whether the risk of environment contamination risk is able to be appropriately monitored and evaluated when aseptic processing is used?
(take monitoring objects, sampling locations, timing, frequency, action limit, etc. into consideration)
(take monitoring objects, sampling locations, timing, frequency, action limit, etc. into consideration)
● Whether contamination risk is underestimated when averaging results of multiple monitoring points?
● Whether impact on product quality has been evaluated in case that microorganism is detected in an aseptic processing area such as Grade A?
6. Catchword
Environmental monitoring is the cornerstone of sterility assurance!!
◇ It is important to properly implement environment monitoring and, based on the results, properly evaluate the necessity of investigation and the impact on product quality!
◇ In the revised version of PIC/S*** Annex 1 to be enforced in the future, the maximum limit for microbial contamination in Grade A is set as “No growth”. Furthermore, it is specified that “for Grade A, it should be noted that for grade A, any growth should result in an investigation.”
◇ In addition to the above, comprehensive activities such as maintenance and management of facilities and equipment, securing operators' qualifications, validation of sterility assurance, etc. are directly linked to the development of a Contamination Control Strategy (CCS).
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