12/18/2020 FDA FY2019 Drug Inspection Observations And Trends

Guest Column | December 6, 2019

FDA FY2019 Drug Inspection Observations And Trends

By Barbara Unger, Unger Consulting Inc.

A comprehensive GMP intelligence program includes monitoring of health

authority enforcement actions, including FDA Form 483s, Establishment
Inspection Reports, warning letters, recalls, import alerts, consent decree
agreements, and EU reports of GMDP noncompliance. This article presents the
most recent publication of GMP drug inspection data from CDER, which
addresses drug inspections conducted in FY2019. The FDA published data from
FY 2018 in September 2019 and we recently addressed that data; FY2019 data
was published on Nov. 15, 2019. Here we examine data from FY2019, along with
seven years’ worth of trends in drug GMP inspections.

The presentation of some data herein differs from data presented on the FDA
website, even though it uses the same raw data. For example, I combine all observation listings that cite 21 CFR 211.42 into a single
value, rather than identifying them in separate line items with the exact same citation text. The FDA largely seems to have taken a
similar approach to mine this year. For example, in the past, observations citing 211.192 were divided into multiple line items; this year
they are consolidated into a single line item.

The FDA’s data includes only Form 483s issued through its electronic system; it does not include Form 483s issued to API
manufacturers, because §211 is not applied to those manufacturers, or Form 483s issued outside of the electronic system. Thus, the data
does not represent the FDA's complete collection of inspection observations for the year. In past years, this data represented
approximately one-third of all Form 483s issued, so conclusions must be tempered by the relative incomplete nature of the data.

Executive Summary:

The number of Form 483s included in this analysis continues to increase slightly each year over the past five fiscal years, ranging
between 645 and 779 inspections (Table 1, row 2 and Figure 1).
The number of observations citing failures in §211.192 (investigation of discrepancies) was displaced from the top of this list in
FY2018 for the first time since before FY2013. In FY2019 it moved up to second place from third place in FY2018 (Table 1, row 3).
In FY2018, §211.160(b) (Lab controls should include scientifically sound specifications) was in first place and fell to fourth place
in FY2019.
Six specific §211 citations increased markedly between FY2018 and FY2019 and one decreased (Figure 3).

FDA Form 483 Inspection Observations

Table 1 shows only the 15 most frequent inspection observation citations between FY2013 and FY 2019, while the tabulation on the FDA
website shows all citations used in the fiscal year. The FDA uses the term “frequency” to represent the number of times the agency
identified a specific citation in its tabulation. Table 1 presents those observations from the highest to lowest number for FY2019,
modified as described in the Introduction section of this article. Both Table 1 and Figure 1 show consistency in the years between
FY2013 and FY2017 with respect to the identity of the 15 most frequent inspection observations.

Figure 2 shows all of the most frequent 15 citations for the three fiscal years, 2017 through 2019. The four most frequently cited
regulations in FY2019 include:

§211.22(d) Procedures applicable to the quality unit shall be in writing and shall be followed moved from second place last year
to first place this year.
§211.192 Investigations of discrepancies moved from third place last year to second place this year.
§211.42(c) Facilities shall include defined areas of sufficient size
§211.160(b) Lab controls should include scientifically sound specific was fourth place last year and third place this year.

FY2019 saw changes in the frequency of seven observation citations that merit mention. These are highlighted in Table 1. Figure 3
shows only the seven citations with notable differences between FY2018 and FY2019. The frequency for citation of 211.160(b), Lab
controls should include scientifically sound specifications, fell from first place in FY2018 to fourth place in FY2019. Six regulations saw
a significant increase in the frequency with which they were cited between 2018 and 2019. This includes:

§211.100(a) Production and process controls shall be supported by written procedures

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§211.188 Master production and control records

§211.113(b) Control of microbiological contamination)
§211.25(a) Personnel qualifications
§211.165(a) Appropriate lab tests shall be used to determine conformance to specifications
§211.67(b) Equipment cleaning and maintenance

It is interesting that the frequency of citation for §211.113(b) decreased consistently since FY2015, until it increased markedly this recent
year. The FDA continues to identify sterile drug product manufacture as a high-risk operation, and many warning letters identify
violations for manufacturers of this category of products.

The FDA focus on OTC manufacturers may explain some of the reason that having and following procedures for the quality unit,
§211.22(d), continues at the top of the list. Many times, these firms either don’t have a quality unit or have one that fails to perform basic
GMP responsibilities.

Table 1: Drug GMP Inspections, §211 Citation Frequency by Fiscal Year

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12/18/2020 FDA FY2019 Drug Inspection Observations And Trends

Figure 1: Total number of 438s in the system

Figure 2: Top 15 ctations from 2017, 2018, and 2019

Figure 3: FDA drug regulation citations in FY2017 through FY 2019 — inspections for selected areas

Conclusions

For those who use inspection observations to monitor and improve their quality systems, the FDA’s annual data provides ample
resources against which firms can measure their potential vulnerabilities and gauge the probable focus areas during upcoming GMP
inspections. The shuffling of positions in the top 15 observation areas likely reflects the FDA’s focus on OTC manufacturers, where
fundamental GMP understanding and compliance seems to be missing. Most of the observations at these sites reflect either a basic lack
of understanding of FDA requirements or a conscious decision that compliance with these requirements would represent an
unnecessary cost.

The lack of adequate written procedures and responsibilities for the quality unit, §211.22(d), remains a very consistent citation over the
five years addressed herein, with increasing frequency from FY 2017 through FY2019. Form 483 observations that include text such as
“The quality unit is inadequate…” often result in additional enforcement action, including warning letters.

While §211.192 moved up to second place this year after being in third place last year, it continues to remain an important observation.
A variety of other Part 211 citations increased this year over last year.

About The Author:

Barbara Unger formed Unger Consulting, Inc. to provide GMP auditing and regulatory intelligence services to the
pharmaceutical industry, including general GMP auditing and auditing and remediation in the area of data
management and data integrity. Her auditing experience includes leadership of the Amgen corporate GMP audit group
for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence
program for eight years at Amgen. This included surveillance, analysis, and communication of GMP related legislation,
regulations, guidance, and industry compliance enforcement trends. Unger was the first chairperson of the Rx-360
Monitoring and Reporting work group that summarized and published relevant GMP and supply chain related laws,
regulations, and guidance. She is currently the co-lead of the Rx-360 Data Integrity Working Group. You can contact her at
bwunger123@gmail.com.

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Comments (14) Login

Sort by: Date Rating Last Activity

Sanjay Shetgar · 53 weeks ago +2

Wonderful insights on how the last 3 years have gone by. Broadly nothing is changing significantly which begs the question on What is
that one is missing between the FDA expectations and the organisations understanding. It could be of much value if one could look at the
data trends considering new organisations ( < 10 years ) as against well developed organisations ( > 10 years ).
FDA uses the standard titles for their observations, while specific observations may not entirely reflect the standard titles. There could be
larger insights and deeper understanding when data trending occurs at specific observation level

Reply 1 reply · active 52 weeks ago

Barbara Unger · 52 weeks ago +1

Thank you Sanjay for you thoughts. I do agree that it would be interesting to separate the new organizations from those that are more
experienced. However I don't know how one would access that data except through a completely manual process that would take a
considerable effort. FDA certainly doesn't provide that insight. As to the formality of the text in the observations vs the actual content
of the examples provided, doing this work would face a similar dilemma. Again, a completely manual process going through each and
every observation in the ~ 800 form 483s FDA included in their data from this year. And even more challenging is not knowing which
firms and sites are represented in those almost 800 form 483s. Remember this represents only a subset of the 483s issued by the
FDA so it's not a complete picture. Your suggestions are very thoughtful, but executing them would be an entirely manual process
that may take months.
Regards,
Barbara

Reply

Sanjay Shetgar · 52 weeks ago +1

If this is to be done manually, I agree it takes a lot of time and efforts

Reply

Premnath · 52 weeks ago +1

Useful information for companies who are planning to enter US market. Interesting to note no observations falling under data integrity
related issues this year. Guidelines issued by FDA and other agencies has really helped companies to understand the requirements.
statistics on geographical locations of manufacturing units inspected in 2019 would have given insights as to which region has improved
over the years
Premnath Shenoy

Reply 1 reply · active 52 weeks ago

Barbara W. Unger · 52 weeks ago 0

I agree that having these data on a geographic basis would be interesting! Be careful though with the claims about data integrity
problems, I'm not sure about your statement. FDA rarely, if ever, cites Part 11 for data integrity for electronic records; the predicate
rules are cited, generally those associated with completeness of data, and control of electronic equipment (not just computer
systems). Neither are exclusively data integrity problems though they are often associated with those areas. Ferreting out data
integrity deficiencies from the data posted by FDA would not necessarily be straightforward. I do agree, and I hope the collection of
global authority guidance on the topic has been most helpful. On that note, I do think that WHO is not doing anyone a service with
their recent draft data integrity guidance. It appears to have been stripped of important detail that is valuable to the regulated
industry.

Reply

Dr.Nandan · 52 weeks ago 0

Nice stuff on evaluation part.

FDA should encourage the organization which are well developed and taking opportunity to correct and implement good standards as
expected by FDA .

Reply 1 reply · active 52 weeks ago

Barbara W. Unger · 52 weeks ago 0

I think that "rewarding" good behavior is in the plan with FDA's new inspection paradigm. What kind of reward and how effective it is
in encouraging a well developed Quality System remains to be seen.

Reply

Hemendra verma · 52 weeks ago 0

Very insightful and statistical information provided by the author

Reply 1 reply · active 52 weeks ago

Barbara W. Unger · 52 weeks ago 0

Thank you.

Reply

KetanAgravat 22p · 52 weeks ago +1

Still it's puzzle to see missing link between industry & regulatory authorities e.g. when industry experts investigate any OOS or any
failure with respective expertise, authority still says investigation is not performed upto the expectation.
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is it authority's view or individual investigator's view? every investigator has his/her personal experience & opinion.

Reply 1 reply · active 51 weeks ago

Barbara Unger · 51 weeks ago +1

I do agree that sometimes comments on investigations may seem investigator specific. However there are some common themes
among deficient investigations including but not limited to: root cause was not identified or supported by scientific evidence and the
investigation was not expanded to other lots that may potentially be impacted. Often there will be an accompanying observation for
failure to implement corrective and preventive actions and verify their effectiveness. I do agree that investigations have been a
problem identified by FDA for many years. The firms that do this well have good training for everyone in this topic and have a
dedicated group of more highly trained staff to lead complex investigations. Firms would be well served to think about what an
investigator may expect to see when documenting investigations.

Reply

Ramakant · 51 weeks ago 0

Very insightful information and helps a lot to put additional efforts in a concerning area to ensure overall quality delivery.

Reply 1 reply · active 50 weeks ago

Barbara Unger · 50 weeks ago 0

Thank you, hopefully others find the information useful too!.

Reply

ravi chinchalkar · 11 weeks ago 0

Great Barbara , it would be helpful for us in preparing the data.

Reply

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