1. Whether you reviewed the layout and checked practically in the plant that everything is as per the layout?
2. Whether you ensured that there should not be any dead leg in the system? If so appropriate action has been taken?
3. Whether the qualification of Water system is performed before the water is used for pharmaceutical use in your laboratory, plant and other?
4.Whether people are imparted proper training?
5.Whether there is sufficient control on biofilm formation?
6. Whether the sanitization is performed periodically as per the standard?
7.Whether the microbial testing is performed as per the applicable specification?
8.Whether life of UV lamp is checked to be within the acceptable range?
9.Whether the validation of effectiveness of UV light in water system been performed?
10. Whether water testing is performed as per the standard procedure for all the sampling points and of returned loops?
With above there are many checkpoints that we shall discuss in next post.
Following one case study where firm was issued warning letter due to the non-compliance in the water system;
In this case study following gaps were identified due to which WL was issued to the firm;
1.Firm failed to demonstrate that their water system can consistently meet the minimum United States Pharmacopeia (USP) monograph specifications suitable for drug manufacturing.
2.Firm do not perform chemical analysis of water, and they lack data to support their water system consistently produces water adhering to appropriate microbial limits (total counts, objectionable microbes).
3.Firm stated that they test the water system, but they failed to test their water in 2021. This frequency does not provide meaningful information about the quality of the water used to manufacture the products throughout the year.
4.Firm's system contains a dead leg with no recirculation loop. Inadequate control of water used as an ingredient in oral rinse products increases the risk of contaminated drug products reaching consumers, including pediatric patients.
5. The firm failed to establish adequate finished product testing procedures.
6. The firm send finished product samples to a contract laboratory for microbial analysis. However, they have not adequately evaluated the suitability of the laboratory’s test methods for use with your drug products.
7. Firm use an (b)(4) to quantify fluoride content as part of their finished drug products’ in-house testing. However, firm lack sufficient evidence showing their method is equivalent or better than applicable USP compendial methods.
8. In the response, firm state their water system’s “quality light” assures the system is sufficient, and it is an “effective form of validation of system function.” Firm also state you send your water to a third-party lab for microbial analysis, and you perform (b)(4) testing. In addition, you indicate you are considering incorporating (b)(4) and testing for “(b)(4).”
9. This response was considered inadequate. As firm lack adequate evidence that their water system meets the minimum USP monograph specifications suitable for drug manufacturing, and they fail to adequately address the deficiencies of their water system’s design. In addition, firm do not provide evidence that their proposed corrective actions would address the quality of water system.
10. Furthermore, their response regarding finished product testing fails to provide an adequate evaluation of their contract laboratory’s microbial test methods.
• A comprehensive, independent assessment of the water system design, control, and maintenance.
• A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces water adhering to (b)(4) Water, USP monograph specifications and appropriate microbial limits.
• Regarding the latter, ensure that firm's total microbial count limit for water is appropriate in view of the intended use of the products produced by the firm.
• A detailed risk assessment addressing the potential effects of the water system on the quality of all drug product lots currently within expiry. Specify actions that the firm will take in response to the risk assessment, such as customer notifications and product recalls.
• A procedure for the firm's water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by the firm.
• The current action/alert limits for total counts and objectionable organisms used for the firm's (b)(4) Water system. Ensure that the total count limits for firm's (b)(4) water are appropriately stringent in view of the intended use of each of the products produced by your firm.
• A procedure governing their program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.
• A comprehensive, independent assessment of the laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of the laboratory system.