8/9 June 2021
Taking a look at FDA Warning Letters from the past two years, objections with regard to pharmaceutical water systems are rather seldom. However, when there are complaints, it is the more interesting that the reason for these complaints is mostly the same: missing reliability. What the authority means in this case is the proof that the water system is capable of securely and reliably producing water in the required quality - taking into account for example the fluctuations in the feed water. The necessary means for this purpose are the validation of the water system and the establishment of a monitoring system which continuously verifies the function.
Excerpts from Warning Letters:
1. Failure to validate and monitor the water purification system to ensure that water is of appropriate quality. […] In your response to the observations noted during the 2012 inspection, you indicated your firm's intention to conduct a comprehensive gap analysis of the purified water system. However, you have failed to indicate when you will initiate this gap analysis and when it will be completed. Your firm also failed to detail how you will determine the source(s) of high endotoxin and TOC in your purified water and how your firm will remedy identified problem(s). We note that, for example, your firm installed an endotoxin removal unit on your purified water system in January 2011 in response to the OOS results for endotoxin in the water used for API. However, your firm has not demonstrated that the water produced by the purified water system is now suitable for use in production. The operational parameters and effectiveness of the new endotoxin removal unit have not been qualified. Your firm does not monitor the microbial and chemical attributes of the feed water, and have no assurances that the purified water system is capable of consistently producing water that meets specifications for a given quality of feed water.
2. Your firm failed to assure that your water system is suitably designed and operated to produce appropriate water quality. Regarding the latter, your firm has not established and validated appropriate cleaning and sanitizing schedules for your purified water system. You have hired a water process subject matter expert and taken other steps to strengthen monitoring of the purified water system. Your response is not acceptable because you have not demonstrated that your purified water system is capable of operating in a continuing state of control.
3. [...] your firm failed to subject the water to routine microbiological testing. Furthermore, your firm failed to validate the water system to ensure consistent water quality for drug production and implement procedures for maintaining or monitoring the quality of the water produced.