FDA 2021 483s – Bioresearch Monitoring

The FDA has released the 2021 483 data. With my mind being mostly preoccupied with bioresearch monitoring inspection preparation, let’s look at that data, focusing on the top 10.

CFR Reference in 2021	# 483s 2021	# 483s 2020	# 483s 2019
21 CFR 312.60	90	58	127
FD-1572, protocol compliance	84	54	119
Informed consent	6	4	8
21 CFR 312.62(b)	48	30	60
Case history records- inadequate or inadequate	48	30	60
21 CFR 312.62(a)	13	11	17
Accountability records	12	11	16
Unused drug disposition (investigator)	1	#N/A	1
21 CFR 50.27(a)	9	3	7
Consent form not approved/signed/dated	7	2	6
Copy of consent form not provided	2	1	1
21 CFR 312.64(b)	9	6	7
Safety reports	9	6	7
21 CFR 312.66	8	7	19
Initial and continuing review	6	2	6
Unanticipated problems	2	4	6
21 CFR 312.20(a)	5	1	3
Failure to submit an IND	5	1	3
21 CFR 58.130(a)	4	2	3
Conduct: in accordance with protocol	4	2	3
21 CFR 312.50	3	7	16
General responsibilities of sponsors	3	4	14
21 CFR 50.20	3	5	8
Consent not obtained, exceptions do not apply	3	1	4

Comparison of 2021 Top 10 BIMO 483 categories with 2020 and 2019 data

Based on comparison of number of inspections per year, I am not sure we can really say there was much COVID impact in the data. COVID may have influenced observations, but all it really seemed to do is excaerbate already existing problems,

Key lesson in the data? The GCPs are struggling at accountability of documentation and decision making.

2020 483s on data integrity

Data integrity continued to be a focus of the FDA, though the reduced inspections definitely led to fewer 483s.

Reference Number	Short Description	Long Description	2020 Frequency	2019 Frequency	2018 Frequency
21 CFR 211.194(a)	Complete test data included in records	Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards. Specifically, , ***	15	38	33
21 CFR 211.194(a)(4)	Complete Test Data	Laboratory records are deficient in that they do not include a complete record of all data obtained during testing. Specifically, ***	10	24	28
21 CFR 211.68(b)	Backup data not assured as exact and complete	Backup data is not assured as [exact] [complete] [secure from alteration, erasure or loss] through keeping hard copy or alternate systems. Specifically, ***	6	6	71
21 CFR 211.194(a)(4)	Data secured in course of each test	Laboratory records do not include a complete record of all data secured in the course of each test, including all [graphs] [charts] [spectra] from laboratory instrumentation, properly identified to show the [specific component] [drug product container] [closure] [in-process material] [lot tested] [drug product tested]. Specifically, ***	4	1	28
21 CFR 211.68(b)	Written record not kept of program and validation data	A written record of the program along with appropriate validation data has not been maintained in situations where backup data is eliminated by computerization or other automated processes. Specifically, ***	1	6	71

483s related to data integrity

2020 FDA 483s around change

The yearly database of 483s has been updated by the FDA. Lots will be written on themes as we end the year, so I decided to give a few of my immediate observations.

I find that over time what I focus in on changes, as my jobs evolve and change, and the interests I have shift. However, some things never change, so let us talk change.

Reference Number	Short Description	Long Description	2020 Frequency	2019 Frequency	2018 Frequency
21 CFR 211.100(a)	Changes to Procedures Not Reviewed, Approved	Changes to written procedures are not [drafted, reviewed and approved by the appropriate organizational unit] [reviewed and approved by the quality control unit]. Specifically, ***	8	13	9
21 CFR 211.160(a)	Lab controls established, including changes	The establishment of [specifications] [standards] [sampling plans] [test procedures] [laboratory control mechanisms] including any changes thereto, are not [drafted by the appropriate organizational unit] [reviewed and approved by the quality control unit]. Specifically, ***	4	18	17
21 CFR 212.20(c)	Adverse effects of changes made	You did not demonstrate that any change does not adversely affect the [identity] [strength] [quality] [purity] of your PET drug. Specifically,***	1	1	1

483s related to changes

I think its fair to say the decreases as a result of the pandemic and the reduced inspections.

Over on the device side of things we see:

Reference Number	Short Description	Long Description	Frequency
21 CFR 820.30(i)	Design changes – Lack of or Inadequate Procedures	Procedures for design change have not been [adequately] established. Specifically,***	26
21 CFR 820.40(b)	Document change records, maintained.	Records of changes to documents were not [adequately] maintained. Specifically, ***	6
21 CFR 820.70(b)	Production and Process Change Procedures, lack of or Inad.	Procedures for changes to a [specification] [method] [process] [procedure] have not been [adequately] established. Specifically, ***	5
21 CFR 820.75(c)	Process changes – review, evaluation and revalidation	A validated process was not [reviewed and evaluated] [revalidated] when changes or process deviations occurred. Specifically, ***	5
21 CFR 820.40(b)	Change records, content	Records of changes did not include [a description of the change] [identification of the affected documents] [the signature of the approving official(s)] [the approval date] [when the change became effective]. Specifically, ***	3
21 CFR 820.50(b)	Supplier notification of changes	There is no agreement with [suppliers] [contractors] [consultants] to notify you of changes in the product or service. Specifically, ***	3
21 CFR 820.75(c)	Documentation – review in response to changes or deviations	There is no documentation of the [review and evaluation of a process] [revalidation of a process] performed in response to changes or process deviations. Specifically, ***	1

Device 473s around change

I’m a firm believer that pharma should always pay attention to the medical device side for 483s. A lot of us are combination products now (or will be) and there is always good trends to be aware of.

My key takeaways:

Think change management and not just change control and document control
Computer change controls need to be holistic and system orientated
Have a process that ensures changes are appropriately reviewed and approved
Risk based and evaluate validation
A robust supplier management program is critical, plan for change

Here’s a more detailed checklist to help you evaluate your change system.

FDA 483 data

The FDA has posted the 2019 483 observations as an excel file. The FDA has made these files available every year since 2006 and I find them to be one of my favorite tools for evaluating regulatory trends.

So for example, looking at change related 483 I see:

2019 vs 2018 483 comparison for short description including “change”

Or for data integrity issues:

*2019 vs 2018 483 comparison for short description including “data”*

Very useful resource that should be in the bookmarks for every pharmaceutical quality professional.

ASQ Audit Conference – Day 2 Morning

Jay Arthur “The Future of Quality”

Starts with our “Heroes are gone” and “it is time to stand on our two feet.”

Focuses on the time and effort to train people on lean and six sigma, and how many people do not actually do projects. Basic point is that we use the tools in old ways which are not nimble and aligned to today’s needs. The tools we use versus the tools we are taught.

Hacking lean six sigma is along a similar line to Art Smalley’s four problems.

Applying the spirit of hacking to quality.

Covers valuestream mapping and spaghetti diagrams with a focus on “they delays in between.” Talks about how control charts are not more standard. Basic point is people don’t spend enough time with the tools of quality. A point I have opinions on that will end up in another post.

Overcooked data versus raw data – summarized data has little or no nutritional value.

Brings this back to the issue of lack of problem diagnosis and not problem solving. Comes back to a need for a few easy tools and not the long-tail of six sigma.

This talk is very focused on LSS and the use of very specific tools, which seems like an odd choice at an Audit conference.

“Objectives and Process Measures: ISO 13485:2016 and ISO 9001:2015” by Nancy Pasquan

I appreciate it when the session manager (person who introduces the speaker and manages time) does a safety moment. Way to practice what we preach. Seriously, it should be a norm at all conferences.

Connects with the audience with a confession that the speaker is here to share her pain.

Objective – where we are going. Provide a flow chart of mission/vision (scope) ->establish process -> right direction? -> monitor and measure

Objectives should challenge the organization. Should not be too easy. References SMART. Covers objectives in very standard way. “Remember the purpose is to focus the effort of the entire organization toward these goals.” Links process objectives to the overall company objectives.

Process measures are harder. Uses training for an example. Which tells me adult learning practice is not as much as the QBOK way of thinking as I would like. Kilpatrick is a pretty well-known model.

Process measures will not tell us if we have the right process is a pretty loaded concept. Being careful of what you measure is good advice.

“Auditing Current Trends in Cleaning Validation” by Cathelene Compton

One of the trends in 2019 FDA Warning letters has been cleaning. While not one of the four big ones, cleaning validation always seems relevant and I’m looking forward to this presentation.

Starting with the fact that 15% if all observations on 483 forms related to leaning validation and documentation.

Reviews the three stages from the 2011 FDA Process Validation Guidance and then delvers into a deeper validation lifecycle flowchart.

Some highlights:

Stage 1 – choosing the right cleaning agent; different manufacturers of cleaning agents; long-term damage to equipment parts and cleaning agent compatibility. Vendor study for cleaning agent; concentration levels; challenge the cleaning process with different concentrations.

Delves more into cleaning acceptance limits and the importance of calculating in multiple ways. Stresses the importance of an involvement of a toxicologist. Stresses the use of Permitted Daily Exposure and how it can be difficult to get the F-factors.

Ensure that analytical methods meet ICHQ2(R1). Recovery studies on materials of construction. For cleaning agent look for target marker, check if other components in the laboratory also use this marker. Pitfall is the glassware washer not validated.

Trends around recovery factors, for example recoveries for stainless tell should be 90%.

Discusses matrix rationales from the Mylan 483 stressing the need to ensure all toxicity levels are determined and pharmaceological potency is there.

Stage 2 all studies should include visual inspection, micro and analytical. Materials of construction and surface area calculations and swabs on hard to clean or water hold up locations. Chromatography must be assessed for extraneous peaks.

Verification vs verification – validation always preferred.

Training – qualify the individuals who swab. Qualify visual inspectors.

Should see campaign studies, clean hold studies and dirty equipment hold studies.

Stage 3 – continuous is so critical, where folks fall flat. Do every 6 months, no more than a year or manual. CIP should be under a periodic review of mechanical aspects which means requal can be 2-3 years out.