Pharma 483s Speaking the Language of QbD

Sandoz's Wilson, NC, plant received an August 12 483 from FDA over failure to use proper validation measures for testing lots of its beta-blocker Metoprolol Succinate ER tablets. FDA writes: a) Failures were noted in the process validation studies performed on the Metoprolol Succinate ER 50 mg tablets. Process validation lot MF001088 failed content uniformity at high speed compression, and process validation lot MF001089 failed dissolution at high hardness for the 4 hour time point. In response to these failures, your firm obtained additional samples from other commercial lots that were unrelated to the validation study. Note the QbD-inspired language contained within the Agency's admonishment of the procedures: In your April 29, 2008 response to the FDA 483, you stated that your firm will continue releasing Metoprolol Succinate ER Tablets because routine product testing of manufactured lots is sufficient proof that the process is validated. We disagree with your assessment. Product testing alone is not sufficient to assure that a process consistently produces a product with predetermined specifications. Adequate process design; knowledge and control of factors that produce process variability: and successful process validation studies, in conjunction with product testing, provide assurance that the process will produce a product with the required quality characteristics. Your firm's validation efforts have revealed that you have not properly studied and established the relationships between compression forces, dissolution, and content uniformity. Also, it is not acceptable to disregard the findings in one of the lots by stating that another lot made under the same process had sample results that met the criteria. To the contrary, this is an indication that you have not identified, and are unable to control, those factors that cause variability in the process. This also indicates that you lack a robust process design. Consequently, you do not have a high level of assurance that the process is in a state of control and is capable of consistently producing a product that meets specifications. Let those who ignore the Agency's commitment to Quality be forewarned. --PWT
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