Understanding Cleanroom

Understanding Cleanroom Classifications
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Mon, 03/24/2014 - 1:36pm
by Jeanne Moldenhauer
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Over the past few years there has been an increasing trend to change from previous
classification systems used to the ISO classification systems in ISO 14644-1. However, many
companies have continued to use the traditional Class 100, 10,000, 100,000 room classification
system from Federal Standard 209-e. In Europe, the GMPs as stated in Annex 1 utilize another
systemGrades A through D.
Many global companies choose to use this classification system. All of these systems are
acceptable for use. However, we have also tended to link the systems together, e.g., ISO
5/Class 100/Grade A. This type of linkage is seen in the FDAs Guidance for Aseptic Processing
(2004). If you are manufacturing an aseptic product and use this linked classification system it
is not likely to be an issue. However, if you are not manufacturing an aseptically processed
product, choosing to link the classification systems together may lead to other consequences.
Federal Standard 209e
This document was written for use by federal agencies of the United States. The scope of this
document is defined as:
This document establishes standard classes, and provides for alternative classes, of air
cleanliness for cleanrooms and clean zones based on specified concentrations of airborne
particles. It prescribes methods for verifying air cleanliness and requires that a plan be
established for monitoring air cleanliness. It also provides a method for determining and
describing concentrations (U descriptors) of ultrafine particles
Equally important are the limitations identified in this document, including:
The requirements of this document do not apply to equipment or supplies for use within
cleanrooms or clean zones. Except for size classification and population, this document is not
http://www.cemag.us/articles/2014/03/understanding-cleanroom-classifications
02-Jun-16
Page 2 of 10
intended to characterize the physical, chemical, radiological, or viable nature of airborne

particles. No universal relationship has been established between the concentration of airborne
particles and the concentration of viable airborne particles. In addition to the need for a clean
air supply that is monitored for total particulate contamination and that meets established
limits, special requirements are necessary for monitoring and controlling other forms of
contamination.
Based upon these limitations, no requirements existed for the viable microorganisms allowed to
be present in support of these classification systems. This system utilized classifications Class
10/Class 100/Class 10,000 and Class 100,000. It also included references to an M system
classification.
This document was subsequently retired and replaced by ISO 14644-1.
ISO 14644-1 classification system
ISO 14644-1, Cleanrooms and associated controlled environments-Part 1: Certification of Air
Cleanliness document, was formally issued in 1999. This document establishes the certification
requirements for air cleanliness areas. This document has replaced the old Federal Standard
209-e (Class 100, 10,000 and 100,000 designations). Within this document the various
classification systems are based upon the requirements for counts associated with non-viable
particulates. The limits stated in this document are depicted in Table 1.
This document
does not include
specific
requirements for
sterile or nonsterile product,
nor does it
include
requirements for
any parameter
excluding nonviable
particulates. As
such, unlike the
FDAs Aseptic
Processing
Table 1: Selected airborne particulate cleanliness classes for cleanrooms and clean zones.
Classification Parameters from ISO 14644-1.
Guidance and the

EUs GMPs Annex
1, there are no
specified limits for viable microorganisms present.

FDAs Aseptic Processing Guidance
In the FDAs Guidance for IndustrySterile Drug Products Produced by Aseptic Processing
Current Good Manufacturing Practice (2004)which is limited in scope to the manufacture of
medicinal products using aseptic processingthere is a similar chart which includes the
02-Jun-16
Page 3 of 10
requirements for both viable and non-viable microbial counts as part of the classification
system. This classification system is depicted in Table 2.
Footnote b of this table indicates that ISO 5 particle concentration is equal to Class 100 and
approximately equal to EU Grade A. However the microbiological limits in this document are
only applicable to aseptic processing. This statement has led many to arbitrarily equate ISO 5,
Class 100, and Grade A routinely. This statement of equality is frequently shown in published
literature and industry documents.
The European Unions GMPs Annex 1
For the European Union, the Drug GMPs are part of EudraLex, The Rules Governing Medicinal
Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice
Medicinal Products for Human and Veterinary Use. This document is supplemented by Annex 1
Manufacture of Sterile Medicinal Products (corrected version). Annex 1 applies to drug products
manufactured by aseptic processing and/or terminal sterilization. Note: Annex 1 section 5
states: For classification purposes EN/ISO 14644-1 methodology defines both the minimum
number of sample locations and the sample size based on the class limit of the largest
considered particle size and the method of evaluation of the data collected. This document
includes a table of limits for microbial contamination. This data is included in Table 3.
Table 2: Classification Parameters from the FDAs Aseptic Processing Guidance
While the tables indicate that these are recommended limits, there is a clear expectation from
European investigators that companies will meet these limits on a consistent basis if they are
going to claim a specific classification for a room.
Additionally, Annex 1 section 9 indicates:
For Grade A zones, particle monitoring should be undertaken for the full duration of critical
processing, including equipment assembly, except where justified by contaminants in the
process that would damage the particle counter or present a hazard, e.g. live organisms and
radiological hazards. In such cases monitoring during routine equipment set up operations
should be undertaken prior to exposure to the risk. Monitoring during simulated operations
should also be performed. 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. It is accepted that it may not
always be possible to demonstrate low levels of 5.0 m particles at the point of fill when
filling is in progress, due to the generation of particles or droplets from the product itself.
02-Jun-16
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In addition to requirements for microbial contamination, Annex 1 contains a table to specify the
requirements for particulate contamination. Table 4 summarizes these requirements.
Annex 2 of the European Unions GMPs is entitled Manufacture of Biological Active Substances
and Medicinal Products for Human Use. Within this document, item 6 is relevant to the use of
controlled environments in the manufacturing process:
6. Manufacturing and storage facilities, processes and environmental classifications should be
designed to prevent the extraneous contamination of products. Prevention of contamination is
more appropriate than detection and removal, although contamination is likely to become
evident during processes such as fermentation and cell culture. Where processes are not closed
and there is therefore exposure of the product to the immediate room environment (e.g.,
during additions of supplements, media, buffers, gases, manipulations during the manufacture
of ATMPs) control measures should be put in place, including engineering and environmental
controls on the basis of QRM principles. These QRM principles should take into account the
principles and guidance from the appropriate sections of Annex 1 to EudraLex, Volume 4, when
selecting environmental classification cascades and associated controls.
ICH Q7A
ICH Q7 is the Good Manufacturing Practice for Active Pharmaceutical Ingredients issued by the
International Conference on Harmonisation Regulations. This is a recognized document for both
the United States and Europe. The scope of this document states: This Guide applies to the
manufacture of APIs for use in human drug (medicinal products). It applies to the manufacture
of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The
sterilization and aseptic processing of sterile APIs are not covered by this guidance As such,
it relates to the manufacture of non-sterile APIs and sterile APIs during the non-sterile stages.
Section
8.5 of ICH
Q7 is
entitled
Table 3: EU GMPs Annex 1 Recommended Limits for Microbial Contamination
Contamination Control. The requirements as stated in this document are:

8.50 Residual materials can be carried over into successive batches of the same intermediate
or API if there is adequate control. Examples include residue adhering to the wall of a
micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and
incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material
to the next step in the process. Such carryover should not result in the carryover of degradants
or microbial contamination that may adversely alter the established API impurity profile.
8.51 Production operations should be conducted in a manner that will prevent contamination
of intermediates or APIs by other materials.
02-Jun-16
Page 5 of 10
8.52 Precautions to avoid contamination should be taken when APIs are handled after
purification.
This section has no requirements for the use of classified areas nor does it have specific
requirements for microbial monitoring of the processes.
Section 18 of this document provides specific guidance for APIs manufactured by cell
culture/fermentation.
Section 18.15 states:
Appropriate and environmental controls should be used to minimize the risk of contamination.
The acceptance criteria for quality of the environment and the frequency of monitoring should
depend on the step in production, and the production conditions (open, closed or contained
systems).
The following requirements are applicable to the cell culture/fermentation process (relative to
air classification and/or environmental monitoring and harvesting, isolation and purification
steps):
18.30 Where aseptic addition of cell substrates, media, buffers, and gases is needed, closed or
contained systems should be used where possible. If the inoculation of the initial vessel or
subsequent transfers or additions (media, buffers) are performed in open vessels, there should
be controls and procedures in place to minimize the risk of contamination.
18.31 Where the quality of the API can be affected by microbial contamination, manipulations
using open vessels should be performed in a biosafety cabinet or similarly controlled
environment.
18.40 Harvesting steps, either to remove cells or cellular components or to collect cellular
components after disruption should be performed in equipment and areas designed to minimize
the risk of contamination.
18.43 If open systems are used, purification should be performed under environmental
conditions appropriate for the preservation of product quality.
Reviewing all of the ICH Q7 requirements, there are no designated systems for classification of
biosafety cabinets or laminar airflow hoods. Additionally there are no specified requirements for
microbiological monitoring of these areas other than they should be appropriate to minimize
risk of contamination and provide appropriate conditions for preserving product quality.
Aseptic processes
When using these documents, the linked form of Class 100/ISO 5/Grade A can be easily
used. Although there are some small differences in the documents, these differences can be
easily resolved, e.g., microbiological limits of 1 cfu in the aseptic guidance and <1cfu in the
European GMPs. The difference in this case being whether you can average results to
determine whether the limits are met for each parameter. Usually the tightest limit is used.
02-Jun-16
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Table 4: EU GMPs Annex 1 Recommended Limits for Particulate Contamination
The problem
So many companies have seen the linked classifications, e.g. Class 100/ISO 5/Grade A, that
they routinely use this classification system in their facility regardless of the type of
manufacturing process. If, for example, you are manufacturing a non-sterile bulk drug or a
terminally sterilized drug and you utilize this classification link, you are choosing to utilize the
microbiological limits for Grade A, which were designed for the production of sterile medicinal
products. Additionally, non-sterile manufacturers rarely have in place the other requirements of
a Grade A facility including things like: changing rooms, cascading room classification, gowning
requirements, and the microbiological control limits and frequencies. It isnt even likely that the
process required the level of control specified for Grade A.
This scenario changes somewhat if the non-sterile bulk is also a biologic product. In Annex 2, it
indicates that one needs to take into account the requirements for classification and cascading
room classifications specified in Annex 1. There are provisions to utilize quality risk
management procedures when considering this requirement. For example, you may have a risk
analysis and control program that shows the microbiological control procedures may not be
required for your process at the levels stated for the specified room grade.
For companies that manufacture products for both the United States and Europe, should you
choose to utilize a classification system other than the Grades A through D it is crucial that you
have a document that explains the relationship of your classification system to the European
classification system.
It is very important that you understand the implications of the classification system you use
and to use them wisely.
References:
EU (2008) EudraLex The Rules Governing Medicinal Products in the European Union Volume 4
EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary
Use.
Annex 1 Manufacture of Sterile Medicinal Products (corrected version). European
Commission. Brussels. 25 November 2008 (revised).
EU (2012) EudraLex The Rules Governing Medicinal Products in the European Union Volume 4
EU Guidelines for Good Manufacturing Practice for Human and Veterinary Use. Annex 2
Manufacturer of Biological Active Substances and Medicinal Products for Human Use. European
Commission. Brussels. Deadline for coming into compliance 31 January 2013.
(SANCO/AM/sl/ddg1.d.6(2012)860362)
02-Jun-16
Page 7 of 10
FED-STD-209e (1992) Federal Standard 209-e Airborned Particulate Cleanliness Classes in

Cleanrooms and Clean Zones. This standard is approved by the Commissioner, Federal Supply
Service, General Services Administration, for the use of all Federal Agencies.
FDA (2004) Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing
Current Good Manufacturing Practice. U.S. Department of Health and 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) Pharmaceutical CGMPs
ISO (1999) International Standard 14644-1: Cleanrooms and associated controlled
environments-Part 1: Certification of Air Cleanliness. International Organisation for
Standardisation. Switzerland.
ISO (2003) International Standard ISO 14698-2:2003 Cleanrooms and associated controlled
environments Biocontamination control Part 2: Evaluation and interpretation of
biocontamination data
FDA (2001) ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients
Jeanne Moldenhauer is the Vice President of Excellent Pharma Consulting. She has over 25
years of experience in the pharmaceutical, biotech, and device industries. She is very active in
PDA, has authored many books and articles, and can be reached at info@excellpharma.com.
This article appeared in the March 2014 issue of Controlled Environments.
TOPICS
CLEANROOMS
REGULATIONS/STANDARDS
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