WHITEPAPER

Cleanroom Routine Environmental Monitoring –FDA Guidance on 21CFR part 11 Data Integrity
Abstract
A recent report suggests that circa 79% of 483 warning letters issued by the FDA to the biopharmaceutical industry
sited deficiencies in their data integrity1. Despite guidance from the FDA, cleanroom environmental monitoring
remains an intensely manual process, with many opportunities for human error to create gaps and errors in the data.
In their 21CFR part 11 guidance, the FDA have given recommendations on what good data integrity looks like and thispresentation explains their advice in the context of current cleanroom environmental practices and shows how theFDA guidance can be applied to improve data integrity.

Cleanroom Routine Environmental Monitoring
30 to 50 trillion
microbes on andinside the humanbody. Humans shed
30,000 skin cell perhour, approximately
3.6 kilos/year

Figure 1. Human skin and microbes

Of course the FDA mandates the air quality conditions forbio/pharmaceutical production in cleanrooms. In fact the real danger
is the microbes on the human body. Humans shed around 30,000 skin cells
per hour2, all of which are potential carriers of microbes. Unfortunately we
do not currently have technology to detect airborne microbes real-time.
So air particle counters are used as a surrogate.
Discussions between the author and Environmental Monitoring Managers
at facilities across the world suggest highlights an increasing trend where
the burden of carrying out environmental monitoring is moving away fromthe QC microbiology team over to the production staff, for two reasons:a) microbiology staff are relatively expensive to employ to carry out suchroutine tasks and b) it reduces the number of people inside the cleanrooms,
thus reducing the potential for product contamination. However, theproduction team do not have the same level of knowledge about routine
environmental monitoring and this is creating challenges itself.

• Increasing regulator
burden• Responsibility passing from
QC to production team
• 1,000’s of data
points/month

Figure 2. Risks to environmental monitoring data integrityIn larger biopharmaceutical manufacturing plants, there can be teams 10 technicians or more whose job it is every
month to take thousands of routine environmental monitoring samples. At each location, they have to manually typethe location name into the counter before they start sampling. Counters have to be manually configured following
written SOPs. At the end of each day, the paper print outs from each sample location have to be photocopied because
the printers in the particle counters are thermal and the print-outs fade over time. Then the results from every location
have to be manually transferred into electronic format one by one.

Touch-Point 1

Touch-Point 2

Touch-Point 3

Touch-Point 4

Touch-Point 5• Ensure correct SOP• Manually Type eachand every sample
location nameManually Configure
counter:• Take paper print-out
and photocopy• Manually transcribe
results• Read and understand
SOP• Sample time,• Number of samples• Results averaging• Correct multiplier
for m3Figure 3. Manual Routine Environmental Monitoring SOPs

Following environmental data errors, a typical response is to mandate re-training for the team. However, the industry
and the FDA is gradually coming to the conclusion that this does not solve the problem it merely treats the symptoms
for a short while until human error starts to creep in again and that the correct way forward is to reduce manual steps
in the SOP in order to reduce the human errors and make the whole process more robust.

FDA Guidance on Data Integrity
In their guidance on the implementation of their 21CFR part 11 data integrity rule3, the FDA use the acronym ALCOA,
where they define good data integrity practice as creating records that are Attributable to the technician carrying out
the testing, are Legible, are created Contemporaneously, Original and Accurate.
In this case Attributable means that the records should somehow be traceable to the technician who did the test.
They should also include a label stating where the sample was taken and the date and time it was taken.
The record of course is required to be legible, which implies that hand-written records are not acceptable. The FDA
goes on to suggest that electronic records should be stored in a format that is open and can be read on many
computing formats so that it will be accessible and readable for years to come. The FDA recommends typical formats
such as PDF, XML or SGML3.
In this instance the word contemporaneously implies that the electronic records should be created immediately thesample is measured, implying that manual transcription of paper records is not good practice and that collating paper
records and then manually transcribing them into electronic format at a later time/date is not good practice.
Naturally the electronic records should be accurate. This implies that the process for capturing those electronic
records should be robust, implying manual calculations and manual data entry where opportunities for human error
exist should be avoided.

Characterized By Ingenuity | 2Now let’s take a look at current environmental practices in the light of the FDA ALCOA guidance. There are many
manual steps in the typical environmental process and usually the paper record does not contain an electronicsignature, so it is not attributable to the technician. Sample locations are manually typed in for each location, inviting
human error and miss-typing, preventing the sample being easily attributed to the sample location. Usually the final
electronic record is legible, but it certainly is not created in a contemporaneous manner, instead the original paper
record is created by a thermal printer and fades over time, so the final record is not the original and, as it is manuallycreated, the final record cannot be guaranteed to be accurate.

No middleware – straightto LIMS/data archive
Daily Cleanroom
EnvironmentalMonitoring• Attributable: electronic signature.
• Legible: PDF• Contemporaneous: electronic record
created at time of test
• Original: no paper – straight toelectronic record• Accurate: no manual counter
configuration or data transcriptions
Secure server

Via wireless
Ethernet

Figure 4. Beckman Coulter MET ONE automated routine environmental monitoring SOPs help with data integrity

Fortunately a more compliant solution exists. Air particle counters from MET ONE can have the sampling SOP andlocations pre-programmed and automated to remove the manual sample location entry and counter configuration
steps. Instead of producing paper records that have to be manually transcribed at a later stage, the counter
instantly generates an electronic record that contains the user’s electronic signature and the sample location name.
This electronic record is in one of the recommended formats from the FDA, PDF, and can be transmitted via wired
or wireless Ethernet to a secure server where the user keeps the final records. This removes all manual configuration
steps, manual location typing and manual data transcription, thus reducing the opportunities for human error andimproving data integrity.

Conclusion
In many cases, cleanroom routine environmental monitoring programs still carry a high risk of human error withSOPs being implemented manually and thousands of data records being manually transcribed into electronic format.
No matter how often staff are trained, the opportunity for error is such programs remains very real, with the associatedimplications for data integrity. The technology exists and is commercially available to mitigate this problem and makethese programs more robust, reducing the impact on data integrity and also supporting the industry’s move towards
environmental monitoring by production staff in the cleanroom.

Characterized By Ingenuity | 3

References
1.

Pharmaceutical Online, An Analysis Of FDA FY2016 Drug GMP Warning Letters By Barbara Unger, Unger
Consulting Inc. https://www.pharmaceuticalonline.com/doc/an-analysis-of-fda-fy-drug-gmp-warningletters-0001, published January 16, 20172.

Health How Stuff Works, How many skin cells do you shed every day? by Ed Grabianowski. http://health.
howstuffworks.com/skin-care/information/anatomy/shed-skin-cells.htm, published July 6, 2010

3.

U.S. Department of Health and Human Services Food and Drug Administration Guidance for Industry, Part 11,
Electronic Records; Electronic Signatures — Scope and Application, August 2003 U.S. Department of Healthand Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center
for Biologics Evaluation and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information,
HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville,MD 20857 USA

About the author
Tony held the Convenorship of the ISO Working Group revising ISO 14698-1 & -2 for microbial control in cleanrooms
and was the UK subject matter expert to the ISO Working Group who revised ISO 14644-1 & -2 for cleanroom
classification and monitoring at the heart of the aseptic manufacturing chapters of both the European GMP and the USA
CGMP documents.
Tony holds a Bachelor’s Degree in Electrical & Electronic Engineering and is employed by Beckman Coulter LifeSciences as a Senior Marketing Manager. Experienced in water system TOC, conductivity and ozone analysis andcleanroom monitoring systems as well as particle characterisation, Tony has spent the last fifteen years in applied
metrology for the pharmaceutical and healthcare manufacturing industries. Prior to that, he worked for companies
providing process control automation solutions for manufacturing industries.
Tony was joint-editor on the ISPE Guide to Ozone Sanitization of Pharmaceutical Water Systems and was also chief
editor of the PHSS Best Practice Guide for Cleanroom Monitoring.
Tony is a well-known international speaker and has provided educational seminars on TOC, liquid particle counting,ozone sanitization for water systems and cleanroom monitoring in UK, France, Italy, India, Malaysia, China, USA,Scandinavia, Ireland, Hungary, Switzerland, Indonesia, Belgium, Greece, Switzerland, Turkey, Egypt, Denmark, Poland,
Italy and most recently Singapore and South Korea.

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product and service names mentioned herein are trademarks or registered trademarks of Beckman Coulter, Inc. inthe United States and other countries.
For Beckman Coulter’s worldwide office locations and phone numbers, please visit “Contact Us” at beckman.com
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