FDA investigators observed employees at Piramal Critical Care’s Bethleham, Pa., plant using potable water in the manufacture of finished drugs, which resulted in a Form 483 [see below].
During the manufacture of inhalational anesthetic drugs isoflurane and sevoflurane, Piramal did not conduct testing for microbial contamination in the water supply, which was used to “clean product contact surfaces such as bulk transfer tanks, finished product stainless steel drums and processing equipment,” the three-observation form states.
The agency went on to chide the drugmaker after the July inspection for an investigation into a lot of sevoflurane that failed acidity and alkalinity testing at 36 months.
“Your investigation determined the root cause of the failure to be the degradation of sevoflurane into hydrofluoric acid due to the presence of metal particles,” the form reads. However, that investigation failed to identify the use of potable water as a potential source of the foreign metal particles.
Whether it’s metal impurities, glass particles, low vials or use of the wrong kind of water, these are impurity risks that you need to avoid. Metal Impurities in Finished Drug Products Dealing with a Changing and Uncertain Landscape will prepare you to comply with the new metal impurities rules issued by ICH — and maybe even teach you some tricks to avoid other contaminants as well. Register today.
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Q: When is an FDA Form 483 issued?
A: An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgement, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.
Q: What is the purpose of an FDA Form 483?
A: The FDA Form 483 notifies the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously.
Q: Is the FDA Form 483 intended to be an all-inclusive list of every possible deviation from law and regulation?
A: No, it’s not. The FDA Form 483 is a report which does not include observations of questionable or unknown significance at the time of the inspection. There may be other objectionable conditions that exist at the firm that are not cited on the FDA Form 483. FDA investigators are instructed to note only what they saw during the course of the inspection. Companies are responsible to take corrective action to address the cited objectionable conditions and any related non-cited objectionable conditions that might exist.
Q: How is the FDA Form 483 shared with the company?
A: FDA Form 483s are discussed with a company’s management at the conclusion of the inspection. Each observation is read and discussed so that there is a full understanding of what the observations are and what they mean.
Q: What are the implications of the FDA Form 483 for agency enforcement and what happens next?
A: The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD&C Act or any of its relevant regulations. The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, all evidence or documentation collected on-site, and any responses made by the company. The Agency considers all of this information and then determines what further action, if any, is appropriate to protect public health.