TOP FOUR OBSERVATIONS RETAIN SIMILAR ORDER TO 2013 AND 2014
Each fiscal year the FDA issues the various FDA 483 Observations from the various Centers to include CBER, CDER, CDRH, etc. This Blog focuses only upon those issued by the Center for Drug Evaluation and Research (CDER) and will concentrate upon those FDA’ CDER listing found within 21 CFR Part 211. Interestingly, while the order of the Observations has remained relatively constant within the top four, the number of Observations has markedly increased in numbers (from 340 in 2012 to 491 in 2013 to 645 in 2014 and 511 in 2015). This appears to be partially because of the large number of Form FDA 483s arising from citations at various compounding facilities.
21 CFR 211.192 was listed as two sets of Observations. The first, which was ranked third in 2014, and again in 2015 was defined as “investigations of discrepancies/failures” (94 Observations 2014; 124 in 2015), while the second set was defined as “written record of investigation incomplete” (38 Observations 2914; 47 in 2015).
Of particular interest to my readers should be 21 CFR 211.113 (b) which pertains to the manufacture of sterile drug products. In 2012 this Observation was considerably lower in terms of numbers of Observations noted (<43) than 2014 when a total of 109 Observations were recorded. Please note that within 21 CFR 211.113(b) that two different sets of Observations were recorded wherein 72 referenced “procedures for sterilizing drug products” (104 Observations in 2015) and 37 referenced “validation lacking for sterile drug products” (53 Observations in 2015).
One should also be aware that the FDA, and CDER, in particular, use an internal electronic system to assist in positioning an Observation. This system called TURBO EIR is designed to provide the most pertinent Observation vs. the information collected by the FDA auditor. While this system is “painted” by the FDA as providing the most fool-proof method of providing the correct citation, it is especially notable within the area of microbiology that this often does not occur and one should question the number of microbiological citations, i.e., 21 CFR 211.113 (a)/(b) – especially when one studies 21 CFR 211.192 and recognizes that several of citations historically should not have been “192”, but 211.113(b).
Reference # Short Description Number of Citations
|21 CFR 211.22(d)||Procedures not in writing, fully followed||160|
|21 CFR 211.160(b)||Scientifically sound laboratory controls||130|
|21 CFR 211.192||Investigations of discrepancies, failures||124|
|21 CFR 211.113(b)||Procedures for sterile drug products||104|
|21 CFR 211.100(a)||Absence of Written Procedures||95|
|21 CFR 211.42(c)(10)(iv)||Environmental Monitoring System||83|
|21 CFR 211.165(a)||Testing and release for distribution||80|
|21 CFR 211.110(a)||Control procedures to monitor and validate performance||69|
|21 CFR 211.67(a)||Cleaning / Sanitizing / Maintenance||68|
|21 CFR 211.68(a)||Calibration/Inspection/Checking not done||64|
|21 CFR 211.166(a)||Lack of written stability program||63|
|21 CFR 211.42(c)(10)(v)||Cleaning System||60|
|21 CFR 211.63||Equipment Design, Size and Location||56|
|21 CFR 211.188||Prepared for each batch, include complete information||56|
|21 CFR 211.67(b)||Written procedures not established/followed||53|
|21 CFR 211.113(b)||Validation lacking for sterile drug products||53|
|21 CFR 211.100(b)||SOPs not followed / documented||52|
|21 CFR 211.25(a)||Training–operations, GMPs, written procedures||50|
|21 CFR 211.192||Written record of investigation incomplete||47|