ASEPTIC FILLING FACILITY RECEIVES SIGNIFICANT OBSERVATIONS
Jubilant HollisterStier located in Kirkland, Quebec, Canada was audited by the FDA on March 19-26, 2012. Following the receipt of the Form FDA 483, the Company responded on April 13, 2012 to the Observations and subsequently on May 1, June 1, and August 9, 2012. The various violations caused the drug products to be adulterated as per Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.
For example:
- Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
For example, on multiple occasions, you failed to perform failure investigations for rejected batches or implement any preventive actions.
The inspection found that your firm failed to perform an investigation for the failure of (b)(4) Injection (b)(4) mg/ml lot (b)(4) to meet in-process pH requirements. This failing pH result was confirmed by your QC laboratory.
Additionally, you rejected filled (b)(4) Injection lot (b)(4) when sub-lots failed to meet the particle in-process acceptance criteria, but did not conduct an adequate investigation into that failure. In your response, you stated that the “…process is known to generate occasional out of limit in-process (b)(4) aggregate particle density results…” However, you did not provide your determination of actual root cause for this failure to meet in-process limits. Additionally, you noted that the sponsor of this product is planning (b)(4) activities for this process and will target consistent particle results as part of the validation of the new process. Please note that your firm is expected to conduct thorough investigations for each failure to meet specifications, regardless of future plans for validation.
In your response to this letter, provide a copy of your revised procedure requiring a thorough failure investigation when in-process or finished product testing shows that your product fails to meet established specifications.
In addition, our investigator found that you do not determine and implement corrective and preventive actions (CAPAs) in a timely manner to prevent recurrence of manufacturing deviations. For example, the inspection noted that some CAPAs remained open for approximately 500-700 days (one was open for 761 days) without implementation of corrections. Your firm’s response stated that you have now completed these CAPAs. However, you failed to address why you had not completed these CAPAs in a timely manner to prevent repetition of manufacturing problems. We are concerned that your response corrects the FDA 483 observation, but does not provide for a systematic and sustainable correction to ensure timely and effective CAPAs.
COMMENT
21 CFR 211.192 represents an all encompassing citation frequently utilized by the FDA. The terminology “failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specification, whether or not the batch has already been distributed” is used within the Agency whenever any issue arises within a batch record and may include areas as far flung as the laboratory or environmental monitoring.
In this particular citation the Agency remains concerned that failure investigations were not performed on a timely basis “when in-process or finished product testing shows that your product fails to meet established specifications”.
The “investigator found that you do not determine and implement corrective and preventive actions (CAPAs) in a timely manner to prevent recurrence of manufacturing deviations. For example, the inspection noted that some CAPAs remained open for approximately 500-700 days (one was open for 761 days) without implementation of corrections”.
“Your firm’s response stated that you have now completed these CAPAs. However, you failed to address why you had not completed these CAPAs in a timely manner to prevent repetition of manufacturing problems. We are concerned that your response corrects the FDA 483 observation, but does not provide for a systematic and sustainable correction to ensure timely and effective CAPAs.”
Again, this above comment represents the often observed “silo effect” wherein the immediate problem is considered, but is not expanded to review the overall effect of the total issue.
Barry A Friedman, PhD LLC 