APPLICATION OVERVIEW

GMP Cleanrooms Classification and Routine
Environmental Monitoring
Introduction
The various GMP guidelines and International ISO standards around GMP cleanrooms are complex andoften appear to give conflicting advice, leading to confusion and sometimes incorrect interpretation.
In the case of Routine Environmental Monitoring, there is very little prescriptive advice and the onus ison the cleanroom owner to devise an appropriate monitoring plan and, in the frequently prescriptive
GMP industry, the lack of direct guidance leaves users struggling to know what to do and thetemptation is to either create over-burdensome monitoring programs or to try to simply use the same
monitoring plan as is used for classification. Both are incorrect: the first because over-burdensome
monitoring programs can lead to more interventions in the critical cleanroom zones and the associatedrisk of contamination events; the second because Routine Environmental Monitoring programs should
be based on a risk assessment of contamination threats to the product during the manufacturing
process and the rules for Classification do not take this into account. For instance, the sampling
locations for monitoring may be very different to those used in classifying the room itself once a risk
assessment shows at what locations in the room the product is exposed to risk.
This paper discusses the differences between GMP Cleanroom Classification and Routine
Environmental Monitoring and explains how Beckman Coulter can help.

What is Cleanroom Classification?
Unlike Routine Environmental Monitoring, Cleanroom Classification is focussed on the cleanroom itself.
If the user does not add additional sampling locations to those defined in ISO 14644-1:2015,
the Classification does not take into account specific areas in the room where the manufacturing
process or product may be at increased risk of contamination. It is a snapshot in time and, whilst it
can be used to trend the cleanroom performance, the typical re-classification interval is annual, so thestatistical validity of the data may be considered weak. Classification demonstrates that the cleanroom
as a whole is in compliance with its intended air particle concentration class/limit at all points inthe cleanroom.
Descrambler
Table

Vial
Sterilising
Tunnel12Filling
Zone

34

5

Capping
StationStoppering
Zone
6

1

Sampling Location
7

Figure 1. Cleanroom Classification to ISO 14644-1:2015 concentrates on the room performance, not risk to the productCharacterized by Ingenuity| 1

Both EU GMP Annex 1:20091 and the FDA CGMP:20042 state that Classification is done to the method
defined in ISO 14644-1:20153. CGMP follows the maximum concentrations defined in ISO 14644-1:2015
for each of the cleanroom grades. GMP Annex 1 has its own particle limits, including a limit for 5 μm
particles* for both classification and monitoring in Grade A, whereas ISO 14644-1:2015 does not define
any limits for 5 μm particles in its equivalent to Grade A, ISO Class 5. (Note: the latest draft of the new
GMP Annex 14 out for public comment at the time of writing this document does not ask the user toclassify using both, but it does require the user to monitor for both 0.5 and 5 μm particle sizes during
routine environmental monitoring programs.

ISO 14644-1:2015:i.

uses a look-up table to define the number of sample locations required to classify a cleanroom

ii. states that the sampling locations should be distributed evenly across the cleanroomiii. requires that the sample probe should be located at the same height as the work activity thattakes place in that part of the cleanroom
iv. states that, where unidirectional airflow is provided, an isokinetic sample probe should beused and it should face towards the source of the airflow, i.e. into the oncoming stream of theunidirectional airflow
v. prescribes that the minimum sample volume taken at each location should be sufficient suchthat it could capture a minimum of 20 particles should that location be operating at themaximum allowable air particle concentration for its cleanroom Class, e.g., if the maximum
number of air particles is100/m3, then a sample of 0.2 m3 would be sufficient to capture 20 particles if the location wereoperating at the maximum allowable air particle concentrationvi. states that, if multiple samples are taken at each location, then the samples at that location
should be averaged.
vii. Concludes that, should all locations have less than the maximum allowable air particle
concentration for the target cleanroom class, then the cleanroom is deemed to have passed
Classification.
EU GMP Annex 1 calls for classification both at rest and in operation:i.

Cleanroom classification should be done at rest with no-one in the cleanroom and also in
operation where the normal number of cleanroom staff are present and normal cleanroom
activities are taking place, e.g. manufacturing.

FDA CGMP emphasises the importance of classification in operation (CGMP uses the term “dynamicconditions”):i.

“It is important for area qualification and classification to place most emphasis on data
generated under dynamic conditions (i.e., with personnel present, equipment in place, andoperations ongoing). An adequate aseptic processing facility monitoring program also willassess conformance with specified clean area classifications under dynamic conditions on aroutine basis.”

What is Routine Environmental Monitoring?
Unlike Classification, Routine Cleanroom Monitoring is undertaken daily for the critical zones andweekly for the less critical areas so the data can be used to trend the overall cleanroom contaminationlevel over time. Sampling locations are focussed on monitoring the contamination risk at locations
where the manufacturing process or product may be at increased risk of contamination. It is doneto demonstrate both that the contamination risk areas are operating correctly prior to the start ofmanufacturing and also during the manufacturing itself.
Unlike Cleanroom Classification where the minimum number and location layout for the air particle
sampling is well defined, the sample locations for Routine Monitoring are not fixed. Instead they

Characterized by Ingenuity | 2

are specific to each individual process and to be determined by the process owner using a risk
assessment, i.e. Routine Environmental Monitoring sampling should be done at locations which might
put the product at risk from contamination. Examples which might put the product at risk are, but notlimited to:•filling zones•

hoppers for vial stoppers•

vial de-scrambler tables•processing equipment,•locations where there may be operator interventions

Figure 2. Routine Environmental Monitoring focusses on locations where the product may be at risk of contamination

Several risk assessment guides are available: two examples include: FDA Q9 Quality Risk Management
Guidance Document4 and the WHO Guidelines on Quality Risk Management TRS-9815 .
Here are some relevant excerpts regarding non-viable air particle counting from the FDA CGMP
guidance:i.

“An adequate aseptic processing facility monitoring program also will assess conformance withspecified clean area classifications under dynamic conditions on a routine basis.”ii.

“Air in the immediate proximity of exposed sterilized containers/closures and filling/closing
operations would be of appropriate particle quality when it has a per-cubic-meter particle countof no more than 3520 in a size range of 0.5 μm and larger when counted at representative
locations normally not more than 1 foot (305 mm) away from the work site, within the airflow,
and during filling/closing operations.”

iii.

“Regular monitoring should be performed during each production shift.”

Characterized by Ingenuity | 3

Figure 3. Routine Monitoring probe should be <1 ft (305 mm) away from exposed productSome relevant excerpts regarding non-viable air particle counting from the EU
GMP guidance:i.

“Cleanrooms and clean air devices should be routinely monitored in operation and themonitoring locations based on a formal risk analysis study and the results obtained during theclassification of rooms and/or clean air devices.”ii.

“The sample sizes taken for monitoring purposes using automated systems will usually be afunction of the sampling rate of the system used. It is not necessary for the sample volume tobe the same as that used for formal classification of clean rooms and clean air devices.”iii.

“The Grade A zone should be monitored at such a frequency and with suitable sample size that
all interventions, transient events and any system deterioration would be captured and alarms
triggered if alert limits are exceeded.”iv. “In Grade A and B zones, the monitoring of the ≥5.0 μm particle concentration count takes
on a particular significance as it is an important diagnostic tool for early detection of failure.
The occasional indication of ≥5.0 μm particle counts may be false counts due to electronicnoise, stray light, coincidence, etc. However consecutive or regular counting of low levels is anindicator of a possible contamination event and should be investigated.”

How can Beckman Coulter Life Sciences help?
Designing and validating your Cleanroom Routine Environmental Monitoring and Classification SOPs
is time consuming and complex. MET ONE 3400+ portable air particle counters can help ensure thatyour SOPs are followed and minimise data errors by offering a level of automation to both processes:
Electronic SOP Maps•

The sampling map, loaded into the counter as part of the SOP, guides users around their daily
monitoring program.

Interactive SOP Maps•

Onscreen instructions at each sample location tell technicians how and where to sample ateach location. As each sample is completed, it turns green on the screen, showing users what
remains to be done at a glance.

Characterized by Ingenuity | 4Electronic SOP Version Control•

The Administrator manages SOP versions in the counter using electronic signatures. Updated
SOPs are automatically replicated across all instruments.

Review and Approve•

Once completed, results can be reviewed and approved in the counter remotely by theSupervisor using a web browser.

Electronic Records•

Once approved, an electronic signature is attached to the final report which can then be
exported in secure electronic format.

Barcode function•

Connect a barcode reader to automatically capture sample location, or production
batch ID, etc.

21 CFR Part 11•

MET ONE 3400+ uses Microsoft Active Directory for User Name and Password Control for
log-on and electronic signatures.

•Each sampling record contains the SOP version number, the user name, the location name,time, date, alarms, counter configuration, sampling results and production batch ID.

•The database is secure and encrypted and the User does not have access to delete records.

•Secure electronic records can be exported straight from the counter.

•Administrator controls the versions of SOP inside the counter and signs-off new versions using
electronic signatures.

•Filter Audit Trail by user, alert level exceeded, failed logins, etc. to quickly provide reports
during audits.

Figure 4. MET ONE 3400+ allows users to create version-controlled interactive SOP sampling maps inside the counter itself, which
instruct technicians where to sample, how to arrange the sampling probe at each location and indicates once sampling at each location iscomplete and allows the supervisor to remotely review and approve the day’s monitoring records remotely via web-browser

Characterized by Ingenuity | 5

Conclusion
Non-viable air particle GMP Cleanroom Classification and Routine Environmental Monitoring are
two very different processes: Classification is to determine that the air quality of the room itself isperforming better than the target class limits and is determined by ISO 14644-1, whereas Monitoringis to determine that the air quality is performing better than the target class limits in locations whereproduct may be at risk as determined by a risk assessment. Both processes can be complex andadding a level of automation through the MET ONE 3400+ can help reduce the risk that incorrect
SOPs are used, that the SOP is not followed correctly and that data errors through human error areminimised, whilst supporting the creation of reviewed and approved electronic records that are 21CFR
part 11 ALCOA compliant.

References1.

European Commission. EudraLex. The Rules Governing Medicinal Products in the European Union.
Volume 4. EU Guidelines to Good Manufacturing Practice. Medicinal products for human andveterinary use, Annex 1: Manufacture of Sterile Medicinal Products, 14th February 2008. EuropeanCommission Enterprise and Industry Directorate-General, B-1049 Bruxelles / Europese Commissie,B-1049 Brussel – Belgium.

2.

Food and Drug Administration. Guidance for industry. Sterile drug products produced by aseptic
processing – current good manufacturing practice, 2004. U.S. Department of Health and Human
Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Centerfor 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

3.

ISO 14644-1:2015 Cleanrooms and associated controlled environments — Part 1: Classification of air
cleanliness by particle concentration. Viewed 19/3/2020: https://www.iso.org/standard/53394.
html

4.

Food and Drug Administration: Q9 Quality Risk Management Guidance Document; https://www.
fda.gov/regulatory-information/search-fda-guidance-documents/q9-quality-risk-management
viewed 15th May 2020

5.

World Health Organisation: Guidelines on Quality Risk Management TRS-981; https://www.who.int/
medicines/areas/quality_safety/quality_assurance/Annex2TRS-981.pdf viewed 15th May 2020

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