Top 25 USFDA- 483/Inspectional Observations & Trending in Pharmaceutical industries(2014-2022)
Sanjeev Kumar Singh
VP & Head- Corporate Quality & RA ||Author||QMS||BITS||IIM-L Alumni||
PREAMBLE
This short article extends the review on analysis and trending on top 25 inspectional observations, called FORM -483 issued by US-FDA on the close of an inspection program in a pharmaceutical firm, this follows a review of last 9 years from 2014 through 2022.
Data analysis is done based on US-FDA open access data available at US-FDA website on inspectional observations, data is organized and analyzed to see the trending in last 9 years have been in various CFR code, objective is to share crisp analysis with pharmaceutical professionals and extends the learning in order to improve health state of Quality system and its sub-systems in order to enhance scale of maturity state of these systems in pharmaceutical industry.
Trend on Number of inspections in last 9 Years from 2014 - 2022:?
Trending reveals that, number of inspections performed in drug category was 5% increase from 2014 to 2015 and then remains almost constant next 3 years (until 2017) and then a marginal increase of 3%, 5% are seen in the year 2018 & 2019 respectively, a significant decline around 54% is clearly apparent owing to Covid-19 pandemic started from early 2020 and continued in 2021.
Recovery trend is seen in 2022 as number of inspections in 2022 is 216% in comparison to 2021 and seems next year/FY-23 should be normal like pre-pandemic time in 2019 & 2018 year. ?
TOP 10 USFDA 483s/Inspectional Observation in last 9 years _2014 to 2022
§?Trending on number of deficiencies recorded during the year 2022 in comparison to 2021 were higher around 200%.
§?Though increase in number of deficiencies is relative to the decrease in number of inspections, this is found to be in-line with number of inspections as number of inspections in 2021 were around 46% in comparison to 2022, and major reason is pandemic effect.
§?Procedures not in writing and/or not fully followed as per 21 CFR 211.22(d) remains to be one of the topmost deficiencies in last 9 years consistently, remains to be on top in last 9 years with 1412 cumulative numbers.
§?Ref. CFR No: 21 CFR 211.192, cited deficiency on Investigations of discrepancies, failures or inadequacy in investigation process remains to be 2nd top-most deficiency in 2022, and this is most area of focus remains to be in 2nd position as cumulative deficiencies in last 9 years, counting 950 observations.
§?Ref. 21 CFR 211.160(b), deficiency on Scientifically sound laboratory controls remains to be on 3rd most recorded observation as per cumulative numbers in last 9 years, however 3rd number is surpassed by 21 CFR 211.100(a), Absence of Written Procedures being the third most cited deficiencies in last two years in 2021 & 2022.
§?An upward shift in observation category- “21 CFR 211.63, Equipment Design, Size and Location” is seen to move on to 5th number against cumulative 10th position as per history of last 9 year , this indicates that facility and equipment design – production area is an emerging area of focus during the inspection.
§?Similarly, an upward movement in observation no – “21 CFR 211.68(b), Computer control of master formula records” is apparent, as it is placed on 6th nos against the 9th position per cumulative trending of last 9 years observations. This indicates that ,computerized system, it’s audit trials review and importantly DI controls is an area to focus on.?
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TOP 11-25 USFDA 483s/Inspectional Observation in last 9 years _2014 to 2022
§?Overall trending in top 11-25th Observations is indicative with an increase of almost 189% in 2022 when compared with 2021, 369 observations against 195 numbers.
§?This represents similar trend in top 10 and cumulative top 25 observations, 1049 in 2022 against the 545 in 2021, almost 192% increase trend. ?
§?This trend further co-relate to number of inspection and number of inspections are almost doubled in 2022 in comparison to 2021, i.e 466 against 215 respectively.
§?Ref CFR Code, 21 CFR 211.42(c)(10)(iv)- Environmental Monitoring System retains as top 11th observations with cumulative observations in last 9 years with 408 observations.
§?Ref . CFR Code 21 CFR 211.67(b)- Written procedures not established/followed is being as 12th observations, though this has surpassed the category against Control procedures to monitor and validate performance which was being on 11th in 2021.
§?Ref. CFR code . 21 CFR 211.110(a)- Control procedures to monitor and validate performance is being the top 12th category of observation when we look at the cumulative numbers in last 9 years with 393 observations.
§?Ref CFR code : 21 CFR 211.166(a)- Lack of written stability program being the top 13th category in cumulative numbers of last 9 years with 393 observations, this is an area in focus during the review to verify compliance to stability management.
§?Cleaning system , Training Ops, and Written record of incomplete investigations are the few observations with are of focus during the inspection program, refer below the Table for the top 11 to 25 categories of observations in descending order.?
Conclusive Analysis & Learning Summary:
§?Overall analysis on top 25 observations of last 9 years shows a rate of 2.4 observations per audit have been and this contributes to 40% on pareto chart analysis against the total observations issued during the FDA inspection.
§?Procedure not followed in full remains to be one of the top most deficiency in last 9 years and retain its first position , this is something to reflect upon and a need of automation to avoid human interventions to adhere compliance to SOP in place as well need to improve quality culture performance.
§?2nd and 3rd category of observations are very close to i.e., investigations of discrepancies, failures & scientifically sound laboratory controls, these areas do require design thinking and certain core tech-competencies on understanding technical requirements, conducting a thorough investigation tech -RCA & CAPA writing , design of right controls in laboratory systems , effective management of OOS investigations.
§?4th category is Absence of written procedure , do require a competent team to design QS & it’s sub-system SOPs to align with the practices , core skills on writing SOPs & tech-documents
§?Rest follows on lack of procedure for sterile ops, cleaning and sanitizing methods, testing and release for distribution, calibrations , computer control over master formula design, equipment design, environmental monitoring, not following written procedure are the few top category of observations being in focus during an inspection program (refer complete list of top 25 observations for details).?
Open access data base to 483s inspectional observations or WLs available at USFDA website provides an opportunity to pharmaceutical industries- professionals to understand the trending on form 483/observations pertaining to various category i.e. drugs, medical device, foods, biologics category etc.
Operations specific observations certainly can help to improve:
Thanks for sharing this insightful analysis on the top 25 USFDA inspectional observations and their impact on the pharmaceutical industry. It's a valuable read for professionals in this field, highlighting the importance of adherence to SOPs and technical competencies to maintain compliance with cGMP standards. The analysis also provides practical recommendations to improve quality systems and sub-systems. Highly recommended!
Executive Regulatory Affair (CMC) @ JAMP India Pharmaceuticals PVt.Ltd.
1 年Great evaluated. The major cause is SOP non- compliance. The root cause of non compliance of SOP is the seriousness to understand the importance of it to implement that can give rise to negligible risk in quality system n second most of time SOP is simplest n well understandable if written well, though written in very complex manner to justify SOP itself.
Lead, ESO BD&L QA at Sandoz Tech Ops / Audit & Compliance, Site Quality Ops, Supplier Qualification/ Sterility Assurance /Oversight Quality & CMO Management/Transfer of projects &Validations/Quality Management System.
1 年Very nicely gathered and presented. This analysis certainly helps industry to self correct and mitigate the gaps.
Pharmaceutical Professional
1 年@Sanjeev Kumar Singh while the observations seems to be too simple to comprehend, it bemuse me. Despite the fact that we have quality professionals across length and breadth, why such observations repeats every now and then? The quality leadership need to Introspect seriously. Are we diligently using our collective experiences and knowledge banks or still believe in "Chalta hai Chalne do" attitude.
President & CEO,Dr.Raghuveer's Pharma Consultants
1 年Very good analysis. This should help the industry to introspect their Quality system.