HOW TO PERFORM A

CLEANROOM VALIDATION AS
PER ISO14644
 Author: Ramon Cayuela
 Published Date: October 10, 2020
Make a Cleanroom Validation in compliance with ISO14644

The validation of the cleanroom shall demonstrate that the production area (in which your products and
components shall be exposed to the environment during its manufacturing process) is suitable and
appropriate under acceptable conditions and parameters of the design in compliance with the international
organization ISO under standard ISO14644.

The cleanroom validation protocol may include the following (14) challenges and testing activities:

1. Room Temperature
2. % Relative Humidity
3. Viable particulate – surface
4. Viable particulate air
5. Non-Viable particulate
6. Pressure Differential
7. HEPA Filter Integrity
8. HEPA Filters Velocities
9. Room Air Changes
10. Room Air Balance CFMs
11. Smoke Test – Airflow pattern
12. Particle Decontamination Test
13. Recovery Test – AHU shut down
14. Sound and Lighting Test
Additional criteria to be considered which affects room cleanliness
should include:
 building finishes and structure
 air filtration
 location of air terminals and directional airflow
 material flow
 personnel flow
 gowning procedures
 equipment movement
 the process is carried out (open or closed system)
 outside air conditions
 occupancy
 type of product
 cleaning standard operating procedures (SOPs).
When is required an HVAC System and Cleanroom validation?
The HVAC and cleanroom validation is performed every time an Environmental Control Area (ECA) is
required and used for GMP manufacturing purposes.

In case that an ECA is used for the cGMP manufacturing process, the HVAC and cleanroom validation is
a mandatory requirement of each environmental controlled area as established by the Federal Register,
section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)).
It will guarantee that all necessary environmental conditions shall be available for the intended use.

The cleanroom validation must be performed after completed the facility and HVAC qualification of all
equipment installation and machinery connections, supplies, air conditioning, water system, compresses
air system, electric power capacity, city water, etc. with their respective commissioning, IQ’s, OQ’s and
PQ’s

Typically, the HVAC validation refers and consider the commissioning or qualification of all utilities and
room related to each product manufacturing operation.

What testing is required in the Cleanroom Validation?

The most common testing performed during a cleanroom validation are:

Airflow or smoke pattern

For the evaluation of this parameter, a smoke generation device is used to add a visible fume in front of
the HEPA Filters or in the area in which the product shall be exposed. The distribution of smoke is
observed, documented, and recorded. It should be uniform following a laminar flow pattern in the exit
direction to return ducts without any major turbulence.

Airflow velocity and changes per hour

For this test, the area of HVAC is divided into hypothetical grids and the air velocity is measured at each
grid and then the average air velocity (V) is calculated. The area of the HEPA filter inlet (A) is calculated
in feet and the total air volume (T) is then calculated by multiplying the average velocity of the air and the
area of the inlet (T = A × V). After this, the volume of the room is calculated and the air changes per hour
are obtained by dividing the total air change by the volume of the room.

Filter leak test

For the leak test of the HEPA filter, a velometer is placed at the front of the AHU system and the air
velocity is checked. The air velocity should be within the higher limit of the HEPA filter.

Particle count – nonviable particle test

A particle counter is used to conduct the test. Particle count is taken at static conditions before the
operation as well as operational working conditions. The particle count should be within the range as per
the standards of particle classification, for example, ISO Class 7, etc.

Viable particle monitoring

Viable monitoring is performed on daily basis by employing the swab test and using nutrient agar medium
for the incubation of microorganisms. The different media plates are exposed in every manufacturing
section. The microorganism count should be within the range otherwise, an investigation must be initiated
to evaluate the root cause, effective corrective and preventive actions

Filter integrity test

The HEPA filter integrity is tested by injecting particles of a predetermined size (0.2 um or greater) using
an aerosol generator into the HEPA filters to determine if they are retaining the aerosol particles. The
100% upward flow of the aerosol must be captured into the HEPA filter. A receptor probe that detects the
aerosol is used to determine if they are passing thru the HEPA filter or not. Each HEPA filter must be
tested and monitored periodically (e.g. annually or every two years). It is important to know if they are
broken. Therefore, the amount of the aerosol detected passing thru it is monitored and documented as part
of the qualification. No residues or traces of aerosol must be detected after the HEPA filter to pass the
acceptance criteria of the filter integrity test.

Pressure difference
It is calculated by making use of the manometer attached to the walls of the adjacent area. The pressure
difference is generally kept positive from the cleanest area to the less clean area in the range from 1 and 20
mmHg pressure.

Recovery test
The recovery of temperature and humidity conditions is checked after losing operational power conditions
or doors opening. For example, the humidity and temperature are checked at the off position of the HVAC
system. Then, the HVAC system is turn -on to verify how much time it takes to recover the expected
conditions, the time required to stabilize the temperature and humidity is noted. Also, this test can be
done, opening the doors during some predetermined amount of time, then document the amount of time it
takes to reach the expected environmental conditions.

Temperature and humidity uniformity test

The uniformity of temperature and humidity are monitored by employing a calibrated datalogger, chart
recorder, thermocouples, thermometer, RTD, manometer, etc. The two parameters are monitored in a
continuous manner, documented in the format and stabilization is ensured within the specified limit.

Fresh air determination

The fresh air intake is observed at the inlet on the fresh air damper. The total air change is calculated. The
intake of fresh air is divided by the total air change in the room and multiplied by 100 to obtain the percent
fresh air intake on each cycle by the HVAC system in all the individual rooms.

How determine or calculate the number of samples required to

classify a cleanroom as per ISO 14644: 2015?
The number of samples to be taken on each cleanroom depends on the area.

The ISO 14644 standard can be used to determine the sampling plan and the number of sampling points to
use during the HVAC system validation. The ISO standards are not free or public domain since it has
copyrights. Refer to the following table as an example.

Area of cleanroom (m2) less than or equal to Minimum number of sampling locations to be
tested (NL)

<1000 See ISO 14644-1 (2015) sampling ta1bles

1000 27
 >1000 See formula A.1 in the ISO 14644-1 (2015)

For a complete table and more information about the iso 14644-1:2015, refer
to httpss://www.iso.org/standard/53394.html
How to prepare a cleanroom validation protocol?
Some people perform the validation strategy following this approach:

Qualification Deliverables HVAC System

CleanRoom AHU Control System

IQ X X X

OQ X X X

PQ X X X

CSV Control System X

The cleanroom validation PQ protocol may include, but, is not limited to the following sections and
information, (as applicable)

1. Purpose
2. Scope
3. General Definitions
4. Safety
5. Reference Documents
6. Responsibility
7. Exceptional Conditions and Discrepancies
8. Strategy: Environmental Monitoring Instructions
 Room Temperature And % Relative Humidity Monitoring
 Differential Pressure Monitoring
 Non-Viable Particulate Monitoring
 Viable Particulate Monitoring
 Air Flow Monitoring and Balancing
 Room Airflow Pattern Test – Smoke Test
 HEPA Filter Air Velocity Test
 HEPA Filter Integrity Test
 Particle Decontamination Test
 Recovery Test – Hvac System Shut-Down and Restore Test
 Room Air Changes Test
 Sound Pressure and Lighting Test
9. Product Disposition
10. Room/Area Certification Parameters Not Meeting Requirements
 11. Documentation
12. Approvals

What is the ISO 14644?

The ISO 14644 is a group of several international standards dedicated to bringing the guidelines related to
the ECA Environmental Controlled Area management.

It establishes the classification of air cleanliness in terms of the concentration of airborne particles in
cleanrooms and clean zones.

ISO 14644 Standards were first formed from the US Federal Standard 209E Airborne Particulate
Cleanliness Classes in Cleanrooms and Clean Zones.
The ISO 14644 is composed of the following documents:
 ISO 14644-1: Classification of air cleanliness
 ISO/DIS 14644-1.2(2014): Classification of air cleanliness by particle concentration
 ISO 14644-2: Specifications for testing and monitoring to prove continued compliance with
ISO 14644-1
 ISO/DIS 14644-2.2(2014): Monitoring to provide evidence of cleanroom performance related
to air cleanliness by particle concentration
 ISO 14644-3: Test Methods
 ISO 14644-4: Design, Construction, and Start-up
 ISO 14644-5: Operations
 ISO 14644-6: Vocabulary
 ISO 14644-7: Separative devices (clean air hoods, gloveboxes, isolators, and mini
environments
 ISO 14644-8: Classification of airborne molecular contamination
 ISO 14644-9: Classification of surface particle cleanliness
 ISO 14644-10: Classification of Surface Cleanliness by Chemical Concentration
 ISO 14644-12: Classification of Air Cleanliness by Nanoscale Particle Concentration
For more information, refer to httpss://www.iso.org/standard/53394.html
For a preview, refer to httpss://www.iso.org/obp/ui/#iso:std:iso:14644:-1:ed-2:v1:en
What is the US FED 209D?
The FED-STD-209 E Airborne Particulate Cleanliness Classes in Cleanrooms and Clean zones was a
federal standard concerning the classification of air cleanliness, intended for use in environments like
clean rooms. The standard-based its classifications on the measurement of airborne particles.

The time before the ISO 14644 was implemented, this legacy document established the 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.

The standard was canceled on November 29, 2001, by the United States General Services Administration
(GSA). The document was superseded by standards written for the International Organization for
Standardization (ISO).
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More details on specific FDA expectations for cleanroom validation can be found in the guidance document
below.

httpss://www.iso.org/standard/53394.html
For a preview, refer to httpss://www.iso.org/obp/ui/#iso:std:iso:14644:-1:ed-2:v1:en
Three (3) options to create a qualification protocol for the cleanroom:
Option 1. You can create a great protocol, using a template.

You can download a free sample of a validation template in .pdf format.

To see the complete list of the most popular validation templates, click here.
In addition, you can request a quotation to buy online a full validation template document in MS Word
format that is completely editable, ready to fill, and adapt to your needs.
Option 2. We can bring you a formal training on how to create your own
validation protocols using our template(s).

This option is recommended if you want to learn more about how to build a robust validation protocol. One of
our expert(s) will provide online step-by-step training to your team (unlimited assistance) on how to build a
reliable validation protocol using a template. You can improve your corporate validation procedures and
policies incorporating our template sections. It includes the template, an exam, and a training certificate for
each assistant. Request a quote now.
Option 3. We can create a customized qualification.

One of our expert(s) will create and prepare for you a customized validation protocol with the inputs and
specific information of your company. It may include, online support in document creation, execution, or final
reporting, Request a quote online.
GET IN COMPLIANCE TODAY, CONTACT US (Hablamos Español)
STATUTORY AND REGULATORY REQUIREMENTS
for cleanroom validation
Validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under
section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following:

“… a drug (including a drug contained in a medicated feed) shall be deemed to be adulterated if the methods
used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform
to or are not operated or administered in conformity with current good manufacturing practice to assure that
such drug meets the requirement of the act as to the safety and has the identity and strength, and meets the
quality and purity characteristics, which it purports or is represented to possess.”
Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement
under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the following:
FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are
provided in 21 CFR parts 210 and 211.

The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-
process material and the finished product meet predetermined quality requirements and do so consistently and
reliably.
Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and
211. The foundation for process validation is provided in § 211.100(a), which states that “[t]here shall be
written procedures for production and process control designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are represented to possess…” (emphasis added). This
regulation requires manufacturers to design a process, including operations and controls, which results in a
product meeting these attributes.
Other CGMP regulations define the various aspects of validation. For example, § 211.110(a), Sampling and
testing of in-process materials and drug products, requires that control procedures “. . . be established to
monitor the output and to validate the performance of those manufacturing processes that may be responsible
for causing variability in the characteristics of in-process material and the drug product” (emphasis added).

Under this regulation, even well-designed processes must include in-process control procedures to assure final
product quality. In addition, the CGMP regulations regarding sampling set forth a number of requirements for
validation:

Samples must represent the batch under analysis (§ 211.160(b)(3)); the sampling plan must result in statistical
confidence (§ 211.165(c) and (d)); and the batch must meet its predetermined specifications (§ 211.165(a)).

In addition to sampling requirements, the CGMP regulations also provide norms for establishing in-process
specifications as an aspect of process validation. Section 211.110(b) establishes two principles to follow when
establishing in-process specifications. The first principle is that

“. . . in-process specifications for such characteristics [of in-process material and the drug product] shall be
consistent with drug product final specifications . . . .”

Accordingly, in-process material should be controlled to assure that the final drug product will meet its quality
requirements. The second principle in this regulation further requires that in-process specifications “. . . shall
be derived from previous acceptable process average and process variability estimates where possible and
determined by the application of suitable statistical procedures where appropriate.”

This requirement, in part, establishes the need for manufacturers to analyze process performance and control
batch-to-batch variability.

The CGMP regulations also describe and define activities connected with process design, development, and
maintenance. Section 211.180(e) requires that information and data about product quality and manufacturing
experience be periodically reviewed to determine whether any changes to the established process are
warranted. Ongoing feedback about product quality and process performance is an essential feature of process
maintenance.

In addition, the CGMP regulations require that facilities in which drugs are manufactured be of suitable size,
construction, and location to facilitate proper operations (§ 211.42). Equipment must be of appropriate design,
adequate size, and suitably located to facilitate operations for its intended use (§ 211.63). Automated,
mechanical, and electronic equipment must be calibrated, inspected, or checked according to a written
program designed to assure proper performance (§ 211.68).
Preparing for cleanroom certification and
validation
Do you know everything that’s needed to get your cleanroom tested?

By Karen von Holtz, CEO of CSI Testing, Inc. and Independent

Certification Services, Inc.
How important is it to know what you are getting into? A good portion of new clients that call me say they
have just finished building their cleanroom and need it tested. It is rare that they understand what kind of
testing is needed beyond particle counting. Often, we find that they do not have a cleanroom that will
meet the needs of their product, and fixing a cleanroom can be more costly than building it correctly in the
first place.

In order to build the best environment for your product, the product must be analyzed during the process
development stage. What kinds of contamination controls are necessary to produce the quality product
you have designed? It probably should have a controlled environment, but what controls should your
controlled environment have? The Institute of Environmental Sciences and Technology (IEST) has two
important documents on design/build/validation of cleanrooms. One is the IEST RP-CC-012
Considerations in Cleanroom Design, and the other is ISO 14644-4 Design, Construction and Start-up of
Cleanrooms and associated controlled environments. (See chart on page 36.)

From those documents, and those of the FDA, you will understand that, at minimum, you need: an
environment that has a controlled access; a clean air supply through HEPA/ULPA filters, which will
provide you with a low contamination environment; an air barrier that consists of the correct amount of
positive or negative air pressure; and the correct number of air changes per hour. Beyond that, there may
be specific conditions for your product, such as a need for a regulated temperature, relative humidity,
special lighting, silicone- or latex-free, and so forth. Furthermore, the documents list items that should be
considered and/or specified when designing your clean environment.

Once the environmental controls are decided on, the next step is controlling the operating environment.
This includes personnel practices (RP-CC-027), operations (ISO 14644-5 and RP-CC-026),
housekeeping (RP-CC-018), garments (RP-CC-003), wiping materials (RP-CC-004), gloves (RP-CC-
005), and more. These documents provide a wealth of information to guide the company in the setup of
operations, writing the SOPs that control the hiring and training of personnel, the cleaning and
maintenance of the cleanroom, and the evaluation of cleanroom supplies.

Prior to full-scale operation, the validation master plan should be finalized. Most often, this should contain
three sections: strategy, protocols, and evaluation.

■ Strategy is the design phase that sets the objectives and specifies the results to be achieved. The
results are specified as permitted residual limits. These may include class level such as ISO Class 7,
amount of room pressure, how many filters, amount of room air changes, lighting, HVAC needs, etc.

■ Protocols cover the implementation stage and will specify how these goals will be achieved.

■ Evaluation describes the means and methods-the tests that will be used to analyze the performance of
the cleanroom.
According to the ISO 14644-2 standard, anytime a cleanroom is put into operation or changes its intended
use, a “validation” must be performed. First-time validation testing takes place over a specified period of
time (usually at least one seasonal cycle) to ensure the cleanroom is functioning as intended and
specified. When changes are made to the cleanroom, an assessment of how the changes will affect the
cleanroom is performed, and a decision is made of how extensive the revalidation will be. Each time a
testing is performed, it is called a “certification,” meaning that the cleanroom is “certified” as meeting the
stated standards, SOPs, and/or design criteria.

Each RP or standard uses a variety of terms for each phase of the testing performed.

■ Phase 1 Installation Qualification, As-Built Testing, or Construction Approval. This is testing that proves
the environment was correctly installed and that it meets the intended design specifications.

■ Phase 2-Operational Qualification, At-Rest Testing, or Functional Approval. This testing is performed
with all the equipment present and operating, but without personnel present. It is necessary to determine
that all parts of the installation operate together to achieve the required conditions. Also, if something
happens to the environment, this testing phase provides baseline data to prove that the environment is
back to a “normal condition” prior to restarting production.

■ Phase 3-Performance Qualification, Operational Testing, or Operational Approval. This is a series of

tests/certifications that are carried out to determine that the completed installation achieves the required
operational performance with the specified process or activity functioning, and with the specified number
of personnel present working in the agreed manner. From this testing data, which is accumulated and
trended, the alert and action limits will be set.

Given all this information, how does one determine which tests to perform? Basically, the room, the HVAC
system, and all the process equipment must be tested to prove they can continually produce the quality
product that was intended and that the process equipment is performing within the intended specification.
However, this article only addresses the cleanroom and its related systems.

There are documents that detail tests, methodology, and recommended equipment for cleanroom testing.
ISO 14644-3 Test Methods recommend test apparatus, test procedures, and acceptance criteria for
determining performance testing. And, IEST has RP-CC-006 Testing Cleanrooms, RP-CC-007 Testing
UPLA Filters, RP-CC-034 HEPA and ULPA Filter Leak Tests, and RP-CC-013 Test Equipment
Calibration or Validation Procedures. Wading through these documents can be a daunting experience. A
qualified independent testing and certification company can help outline an appropriate testing program
for each cleanroom or support room.

Unless your product has special needs, a primary testing program might include:

■ HEPA/ULPA filter installation leak test. This test is performed to verify that the filters have been
properly installed and are free of leaks.

■ Airflow volume, velocity, and uniformity tests. This test is performed to check the uniformity of the
clean air and to verify that there is enough air supply to provide the proper room pressures.

■ Airborne particle count test. This testing verifies that the cleanroom, the personnel, and process
equipment is performing to the intended clean level.

■ Room pressurization test. This test is to verify that there is a proper amount of positive/negative room
air pressure.
■ Microbial testing of air, surfaces, and measurement of the efficiency of the cleaning
process (ISO 14698, Parts 1, 2, and 3).

The newest recommended practice from IEST is RP-CC-019 Qualifications for Organizations Engaged in
the Testing and Certification for Cleanrooms and Clean-Air Devices. This document defines
recommended qualifications for organizations engaged in testing and certification by establishing levels of
competence to be demonstrated by testing personnel. It is intended to provide guidance to equipment
owners when they are assessing the credentials of a prospective testing vendor.

Basically, if you don’t know or understand the way to specify the design aspects of your cleanroom, know
how to specify disposables and cleanroom service or testing, or even know the right questions to ask
service providers, you may not get the information or quality of information that is needed.

One place to go for reliable help and information is the IEST. The IEST is a not-for-profit association
whose members are internationally recognized for their contributions to the environmental sciences in the
area of contamination control. The IEST is a global leader in the development of recommended practices
and standards; and is recognized as an international resource for information on controlled environments
through education and the development of recommended practices and standards. Without an
organization such as this, it is almost impossible to track the most updated international standards.

The IEST can be reached at www.iest.org or at (847) 255-1561.

Karen von Holtz is the CEO of CSI Testing, Inc. and Independent Certification Services, Inc., which
specialize in the testing, certification, and validation of clean environments. She has been active in IEST,
on several working groups writing new standards, and a chair of Working Group 19: Qualifications for
Organizations Engaged in the Testing and Certification of Cleanrooms and Clean-Air Devices.

Guide to commissioning and qualification

Published: 3-May-2019

Design & Build Pharmaceutical

The specific steps companies should follow to complete a cleanroom project, be it a new
build or upgrade, are explained in this guide by Mack Powers, Integrao President
Commissioning and qualification (C&Q) are terms and processes related to the manufacturing of
pharmaceutical or biotechnology products. Each term represents a scope of work that is part of a
larger framework for making sure that a facility —and the equipment in it— will function as
required and be approved by the regulatory agencies that have jurisdiction over that facility.

C&Q is a highly multifaceted process. Such complexity may lead to confusion regarding the
steps required. Indeed, there are several key questions to take into consideration, which can be
identified as the following:

1. What is the purpose or end goal of the process? This is the most important question.
 2. What do commissioning and qualification actually mean?

3. Who are the stakeholders?

4. How do you carry them out at a facility/cleanroom?

5. What are some of the challenges faced?

“Begin with the end in mind” is a quote from Covey, fitting here as it can be easy to forget the
objective of C&Q once you dive into the details.

However, it should never be lost that the goal of the C&Q process is "to obtain a quality product
manufactured in this facility".

For finished products, this quality means the product has been consistently produced with the
proper identity, strength, and purity to ensure safety and effectiveness (efficacy). Also known as
the quality target product profile (QTPP).

Quality also means the manufacturer has quality systems in place and has performed a risk
management assessment of the facility and the manufacturing processes for the product.

Key concepts

The first key term that comes to mind is commissioning; a systematic and documented approach
to the startup and turnover of facilities, building systems, and equipment to end-users. The
results ensure that the design requirements, specification documents, and all stakeholder
expectations are met.

Commissioning verifies that what was specified was installed, that it functions properly, and that
it was successfully turned over to the user. During commissioning, the operations and
maintenance manuals are verified, and personnel are trained. Activities in this phase may include
design reviews, factory acceptance testing, site acceptance testing, and functional testing.

Summary reports are generated after commissioning and are an overview of the results and any
deviations encountered during testing.
Qualification extends beyond commissioning to accomplish the validation master plan
During commissioning, the primary focus is placed on satisfying engineering requirements for
the facility, defined earlier in the project.

Next, qualification refers to the activities undertaken to demonstrate that facilities, building
systems, and process equipment are suitable and perform as specified in project design
documents. Qualification extends beyond commissioning in that it meets the demands and
criteria of the validation master plan (VMP).
Moreover, qualification is primarily concerned with verifying and documenting that the facility,
systems and process equipment that have a direct impact on product quality are rigorously tested
and documented.

In cleanrooms, any system that affects these following parameters will need qualification: air
purity, temperature, room pressure and humidity.

Qualification consist of four parts:

 Design qualification (DQ): the documented verification that the proposed design of the facilities,
systems and equipment is “suitable for the intended purpose”.

 Installation qualification (IQ): The facility and process equipment are installed per the contract
documents.

 Contract documents include all drawings, specifications, piping and instrumentation (P&ID)
diagrams, etc.

 Operational qualification (OQ): The facility and process equipment operate as intended
throughout all anticipated ranges of performance.

 Performance qualification (PQ): The facility and process equipment perform as they are intended
and meet predetermined acceptance criteria over a specified period.
While commissioning can be viewed as primarily an engineering test, qualification testing is
directed with oversight from the quality assurance team. Thus identifying two of the stakeholders
involved in the C&Q process (engineering and quality assurance).

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A team effort

It cannot be understated how important it is to clearly identify who each stakeholder is and what
role each is to play in the C&Q process. Earlier, we confirmed that safety and effectiveness is the
end goal and that there must be a quality system in place to guarantee these.
It would not be possible to develop those systems and subsequently achieve that goal without a
robust and integrated effort between at least the following departments:

 Manufacturing

 Operations

 Engineering

 QA and QC

 Operational and Informational Technologies

Additional stakeholders that will be involved will be any local, regional or national authorities
with jurisdiction in the area of the facility. One of the reasons that each of the stakeholders needs
to be involved in the project early is the FDA stipulation that quality cannot be tested into a
product. This means that quality needs to be designed into the product, the facility and all
processes associated with the manufacturing of that specific product.

To accomplish this, subject matter experts from each team and discipline will need to be part of
the design of the product, facility, and processes from the earliest stages. A suggested starting
point for most companies is to begin the documentation process by developing a user
requirement specification (URS). The URS will be defined further below.
Cleanroom C&Q

What about steps that occur before a URS is written relating to the product itself? The
commissioning and IQ/OQ of a facility and cleanroom are predicated upon previous steps. So
from the beginning, the QTPP for the drug product is defined by the product development and
manufacturing teams, and then critical quality attributes (CQAs) are established.

CQAs are physical, chemical, biological, or microbiological properties or characteristics that

should be within an appropriate limit to ensure the desired product quality.

For example, if the process involves an oral

solid dosage product that requires the use
and mixing of powders, then wouldn’t it be
important to determine the effective relative
humidity range in the suite?
Once the CQAs are established, critical process parameters (CPPs) are identified. These are any
variability that has an impact on a CQA and therefore, should be monitored or controlled to
ensure quality.

The definitions of the CPPs begin to crystalise some of the design requirements for the facility
and processes, and subsequently, what will be required in the C&Q process.

For example, if the process involves an oral solid dosage product that requires the use and
mixing of powders, then wouldn’t it be important to determine the effective relative humidity
range in the suite? Therefore, the HVAC system will need to be designed suitably.

What about where the product or API is highly toxic? What kind of room pressurisation and
room classification will be established to protect the product and/or personnel? These
specifications will be summarised and defined in the following step, which is the creation of the
URS.
The URS is generated as a joint effort between product development, manufacturing, engineering
and quality assurance, with scope including:

 Level-1 Full details of end user operability

 Level-2 Full details of functionality

 Level-3 Software functionality interface

 A full description of the required system performance

 Performance criteria, critical parameters and operating range

 Cleaning and maintenance requirements

 Appropriate regulatory requirements

 Documentation requirements

 Training requirements

 Any required industry standard testing

Once the URS has been approved, the functional design specification (FDS) will be developed.
The FDS will be a collaborative effort between users who developed the URS and the team of
engineers, scientists, vendors, constructors etc., who will be responsible for delivering the project
to meet URS requirements.

No demand from the URS should be unfulfilled by the FDS, and the FDS will need to confirm
that all GMP requirements will be satisfied with the design. These requirements would include
the ability to test all design elements later during commissioning, qualification and validation.

The master plan

Before C&Q can begin, several additional events must occur. These include the final project
design, design review, development of the VMP, and then the construction of the facility.

After completion of the final project design documents, the project might also include an
enhanced design review (EDR). The EDR is “the documented verification that the proposed
design of the facilities, systems and equipment is suitable for the intended purpose”.
The VMP is a high-level documented plan that establishes an umbrella validation plan. It
identifies the layout of the operation, the associated utilities and systems, the equipment, and the
processes to be validated. It also provides information as to the extent of the qualification (IQ,
OQ, PQ), testing requirements, required documentation, acceptance criteria, SOPs, training, and
responsibilities. While these activities are being completed, the project is constructed.

To review. Presented in sequence and at a high level, these include:

 Define the quality target product profile (QTPP)

 Establishment of critical quality

 attributes (CQAs)

 Definition of critical process parameters (CPPs)

 Definition of the user requirement specification (URS)

 Definition of functional design specification (FDS)

 The project design

 Enhanced design review (EDR)

 Development of the validation master plan (VMP)

 Project construction

 Project commissioning

 Installation qualification (IQ)

 Operational qualification (OQ)

Facing the challenge

Frequently asked questions revolve around the challenges in the C&Q of a facility or cleanroom.
Environmental control is one of them.
The primary goal of every project is to deliver safe and efficacious products to the patient.
Therefore, it is imperative that the environmental control of the facility making that product
function is at its optimal performance.

Maintaining environmental control of complex facilities and processes is significant and will
require the integration of industrial automation products, for the process equipment, and building
control systems such as HVAC and the environmental monitoring system.

These systems will probably be sourced from multiple vendors, and will all have to interface
and, in the end, verify that all direct inputs and outputs were within range and under control.

Maintaining environmental control of

complex facilities and processes is
significant and will require the integration of
industrial automation products
An Introduction To Pharmaceutical Facility
Commissioning & Qualification
By Jerry Martin
When looking at facility commissioning and qualification, it's often good to start out
with understanding key words so that everybody's on the same page. When the
pharmaceutical industry uses the terms “commissioning” and “qualification,”
commissioning could be applied to any facility, while qualification is an aspect of
commissioning that refers to a facility that will be operated under good manufacturing
practice (GMP) regulations.

Thus, the first thing a pharmaceutical facility should do is familiarize itself with the
requirements of various regulatory authorities related to good manufacturing practices,
in addition to any relevant local or international laws, codes, and regulations. If
products are to be sold in Europe, the European GMP for qualification and validation
will apply, and in the U.S., the Food and Drug Administration GMP is described in 21
CFR 211.42 on building and facilities.

The U.S. regulation, 21 CFR 211.42, describes the design and construction features
necessary for a pharmaceutical manufacturing facility, including the requirement that
the facility will be of suitable size and construction to both meet the goals of the facility
and conform to GMP regulations. This means thinking in advance about the design of
the facility so that, once built, it accommodates proper cleaning, maintenance, and
operations. This would include everything from properly sizing the facility to provide
adequate space for placement of equipment and designing for the flow and storage of
equipment and materials, to the support operations for those procedures, including
utilities, packaging, labeling, and product storage.

Once design and construction and general commissioning are completed,

pharmaceutical facilities must be qualified and their processes validated. Validation is
the generation of documented evidence that processes are capable of consistently
producing finished product that meets quality specifications. Validation is typically
divided into four qualification phases: design qualification (DQ), installation
qualification (IQ), operational qualification (OQ), and performance qualification (PQ).

1. The DQ outlines everyone’s roles and responsibilities in developing the concept

for the facility — engineering and design teams, trades, subcontractors, and
suppliers — and anticipates the appropriate documentation for the premises,
supporting utilities, equipment, and the processes themselves. The opposite of
DQ would be designing the facility as you think might be suitable, then after
construction, looking to determine whether it meets pharmaceutical GMP
requirements.

Commissioning will be conducted here to ensure a correctly designed and built

facility, with confirmation of water and power utility supply, HVAC systems, waste
removal, etc. All of these things are part of the design for the facility, and once
complete, the institution of those aspects is considered “commissioning of the
facility.” By definition, this doesn’t fall under GMP, which looks only at the aspects
that directly impact product manufacturing or have direct product contact.
2. IQ is a process to compile a documentation package that ensures receipt and
proper installation of the appropriate parts and systems of the process
equipment. This includes, for example, ensuring that all equipment parts are
received and assembled as required, that the electrical and water hookups and
supply levels are correct, and that any other equipment necessary for the
operation is installed and able to deliver per specification. Documentation
ensures that not only is everything accurately installed and performing suitably
but that its performance is verified per the manufacturer's specifications. If the
drug sponsor assumes that equipment is made of a particular grade of stainless
steel, was it actually made of that grade of stainless steel? Does the supplier have
the documentation to show that grade was confirmed? That's the level of detail
that the pharmaceutical manufacturer needs to address to meet regulatory
requirements, whereas the commissioning agent might not examine all those
confirmations.

3. Once that is complete, the next phase is OQ. At this point, the testing during
commissioning is evaluated to ensure that the equipment performs as specified
by the manufacturer. In some cases, that can be done at the supplier (facility
acceptance tests, or FATs), or it could be done after installation at the user (site
acceptance tests, or SATs). Often, initial phases of OQ, including operator
training, can be conducted by the equipment manufacturer, while local site
requirements related to placement, local utility supply, and local operation
confirmation will be done in the user’s facility.

4. PQ is the final stage. It begins with a review of the DQ, IQ, and OQ
documentation, then proceeds to generate data and documentation to confirm
that the installed equipment can perform as the user requires it to perform.

As an example, consider purchasing an oven.DQ ensures you have adequate space,

that it will be electric or gas, as specified, and that it will be equipped with the
appropriate supply lines.IQ confirms you received the model you ordered and all
its associated documentation.OQ confirms that if you set a temperature and time
(up to maximum specifications), the oven operates as it is supposed to, and PQ
confirms that whatever you want to bake comes out as intended under the
required settings.In a pharmaceutical operation, the commissioning team builds
and qualifies operation of the facility.The validation team confirms the facility is
capable of consistently yielding product that meets its quality specifications.
Take a deeper dive into the process in Joanna Gallant's course:

FDA Guidance for Industry “Process Validation: General Principles & Practices” –
Whatever Happened to IQ, OQ, PQ?
From a regulatory perspective, qualification is the responsibility of the end user. With
this liability, the facility owner needs to keep an eye on what they are delegating to the
supplier. Because of this, much can be expected of the supplier, including quality
systems as they relate to equipment fabrication; welding and the assembly, testing, and
calibration of the test equipment at the supplier; and any software quality assurance
associated with it.

FATs, which have some overlap with operational qualification, are crucial to ensure the
supplier and end user agree upon acceptance. After shipping and installation in the
pharmaceutical manufacturing facility, the SAT verifies that installation was performed
correctly and operating specifications are still being met.

In summary, the commissioning of a facility, equipment, or system for operation under

GMP regulations involves qualification that all operations are suitable for the intended
purpose. The facility owner must have traceable verification of the systems, minimizing
punchlist items to improve start-up and eliminate problems up front. Commissioning
verifies that what was specified was correctly installed and that the owner can
reasonably ensure that the next step verifications for this regulated industry will be
successful.

The commissioning agent has that responsibility initially, but once the facility is handed
over to the facility owner (contract manufacturer or drug developer), it becomes the
drug developer or sponsor’s responsibility because it's a regulated pharmaceutical
operation. The drug sponsor doesn’t necessarily have to repeat all of the commissioning
steps, but it does need to satisfy regulators that processes are qualified and validated per
GMP regulation. Almost as important, there must be complete documentation of all
phases. As one FDA reviewer once famously put it, “if it's not documented, it's a rumor.”

About The Author:

Jerry Martin is an independent consultant to pharmaceutical

manufacturers and equipment suppliers for filtration, single-use manufacturing,
marketing, business development, and regulatory compliance. He was previously SVP,
marketing and global scientific affairs, for Pall Life Sciences, where he served the
pharmaceutical, biotech, medical device, and vaccine industries for over 37 years. He is
currently chairman emeritus of the Bio-Process Systems Alliance, the single-use
manufacturing trade association, and a member of the USP Expert Panel on Plastic
Systems Used for Manufacturing Pharmaceutical Products. He holds an M.Sc. in
microbiology from the University of Toronto.

Qualifying your cleanroom

Aug. 12, 2019
Revised GMP guidelines will strengthen emphasis on contamination
control, impacting cleanroom performance qualifications
Jessica Rayser


Technology, manufacturing processes, and regulatory trends have changed in the 10 years since
the last revision to Annex 1 of the EU GMP Guideline for the Manufacture of Sterile Medicinal
Products. With the revised document set for release this year, the updates significantly impact
quality control (QC), quality assurance (QA), and all laboratory activities. This revision is
intended to add detail and clarity and provide global alignment of standards. Even though Annex
1 is a European document, drugs manufactured globally for sale in the EU need to comply with
the standards, which is why Annex 1 was developed in collaboration with global regulatory
bodies such as the World Health Organization and Pharmaceutical Inspection Co-operation
Scheme.

Moreover, with the current economic boom for pharmaceuticals, more companies are expanding
their manufacturing capabilities and opening new facilities. This is particularly relevant as,
according to a survey from the Parenteral Drug Association, industry members find the most
challenging proposed change in Annex 1 to be the qualification of facilities.

Constructing and qualifying a new cleanroom is a huge investment of a company’s money, time,
and resources. Given the purpose of the cleanroom and its role in product quality, there are
extensive regulatory requirements surrounding cleanroom design and validation. With recent
revisions to some of these requirements in ISO 14644 and proposed changes to Annex 1, will
your qualification meet the new standard?

Maintaining compliance
A recent U.S. Food and Drug Administration warning letter highlighted the potential
consequences of failing to comply with GMP standards. In the letter, the FDA made the
following observations regarding facilities and contamination control:

Drug products intended or expected to be sterile were prepared, packed, or held under
insanitary conditions, whereby they may have become contaminated with filth or rendered
injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of
the FDCA.

Your firm failed to establish and follow appropriate written procedures that are designed to
prevent microbiological contamination of drug products purporting to be sterile, and that
include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

Your firm failed to maintain the buildings used in the manufacture, processing, packing, or
holding of a drug product in a clean and sanitary condition (21 CFR 211.56(a)).

Your firm failed to establish an adequate system for monitoring environmental conditions in
aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

To maintain a strong compliance position, it is imperative to start with a solid foundation. A

well-functioning cleanroom starts with good process and cleanroom design and utilizes key
aspects of the well-established quality by design (QbD) methodology (Exhibit 1) and Quality
Risk Management (QRM). The overall contamination control strategy should already be
established and incorporated into the design. The appropriate layout, space, equipment, building
materials, and facilities need to be determined based on the type of product and manufacturing
cycles.
The flow of personnel and materials are critical aspects that also require special consideration.
Annex 1, 2017 draft version section 4.2 states “the maximum number of operators in critical
areas should be determined based on QRM, documented in the contamination control strategy,
and validated during activities such as initial qualification and aseptic process simulations, so as
not to compromise sterility assurance.” It is critical to control people and materials entering the
classified clean areas.

The role of the QC microbiologist

The cleanroom design and qualifications should be overseen by a team representing (but not
limited to) Engineering, Operations, Quality, Facilities and Microbiology. The Annex 1 draft
from 2017 emphasizes the role of the QC microbiologist for all manufacturing processes.
Specifically, in terms of cleanroom qualifications, it states in 2.c that “processes and monitoring
systems for sterile product manufacture must be designed, commissioned, qualified and
monitored by personnel with appropriate process, engineering and microbiological knowledge.”

It is important to recognize the many tasks of the QC microbiologist and their responsibilities
during the planning and setting up a new cleanroom. While QC microbiologists are integral to
the manufacturing design and processes, they are also the primary owner of the microbiology
laboratory. Their overall list of responsibilities is comprehensive and might look similar to this:

 Design the laboratory and workflow

 Order, install and qualify equipment
 Hire and train technicians
 Write and revise SOPs
 Develop an environmental monitoring program
 Establish sampling plans
 Implement and validate QC methods and testing based on release specifications
 Conduct bioburden and endotoxin testing
 Perform microbial identifications
 Investigate out of specifications, deviations and contamination events
 Manage LEAN activities and productivity projects

After the cleanroom design, installation, and operational qualifications, the QC microbiologist
takes the lead for the cleanroom performance qualification. The process performance
qualification (PPQ) studies determine whether an initial state of control has been established. For
example, the FDA stated in a warning letter, “Successful PPQ studies are necessary before
commercial distribution. Thereafter, ongoing vigilant oversight of process performance and drug
product quality is necessary to ensure you maintain a stable manufacturing operation throughout
the drug product lifecycle.”
The performance qualification is when the surface and airborne particulate and bioburden levels
are monitored and tested (see Tables 1 and 2). The qualification is absolutely essential for
determining whether the cleanroom was adequately designed and built to prevent contamination
of the products being manufactured and requires thorough microbiological analyses. A poor
qualification increases risk to manufacturing, the environment, patient safety, and the company’s
investment in the new facility.

Revised guidelines
The revised Annex 1 treats Class A (class 100/ISO 5) and Class B (class1000/ISO 7) equally in
terms of monitoring and requalifications. These areas will need a higher number of sampling
points for the aseptic processing and the immediately adjacent environment (grade A/B) (Annex
1, 2017 draft version: 5.26). Sampling points should include all critical processing locations,
based on risk to the final product. The larger number of sampling points can contribute to a better
understanding of the state of control and potential changes and trends.
Accurate microbial identifications

During performance qualification, the bioburden counts need to be followed by microbial

identification. Understanding the flora in the manufacturing environment serves to direct an
appropriate cleaning strategy, helps determine where the contamination is coming from and what
controls need to be added to protect the product. Risk assessments are an important part of
qualifications, and an appropriate risk assessment cannot be made without an accurate
identification.

The identifications generated during cleanroom performance qualification establish a baseline as

to what flora is found in the manufacturing environment, and are also critical for establishing
alert and action limits. From this information, changes in the manufacturing environment can be
assessed.

According to Annex 1, 2017 draft version: 9.33, “If microorganisms are detected in a grade A or
B zone, they should be identified to the species level and the impact of such microorganisms on
product quality (for each batch implicated) and state of control should be evaluated.
Consideration may also be given to the identification of grade C and D contaminants, and the
requirements should be defined in the contamination control strategy.” It cannot be understated
how important the accuracy and reproducibility of the microbial identifications are, especially
for the initial qualification as it serves as a baseline.

Moreover, the cleanroom qualification is not a one-time event. Cleanrooms should be requalified
biannually, as well as after changes to equipment, facilities or processes. It is clearly stated in the
reviewed Annex 1 guideline (section 5.29) that for grades A/B the maximum time interval for
requalification is six months. For grades C and D, the maximum time interval for requalification
is 12 months.

The requalification gives the opportunity to critically evaluate the microbiological data. The
microbial identifications are just as important during the requalification in order to assess
changes and risk.

The draft Annex 1 also speaks extensively about the importance of trending data on a routine
basis, not just during requalification. To adequately assess changes in flora type and numbers,
there has to be complete confidence and reliability on the previously collected data. Frequent
analysis of trends allows a proactive response to changes in the manufacturing environment. It
helps identify controls to mitigate risk and protect the final product from contamination. It is not
uncommon for regulatory inspectors to request trend reports and objective documentation for
review.

Risks of a failed cleanroom qualification

If the microbial identification method is inaccurate or irreproducible during the performance
qualification, there is a false sense of control, additional time and money wasted to remediate
contamination (both at the time of the qualification and in the future), ineffective action and alert
limits, and delays in manufacturing. Those delays may cause drug shortages which would have a
direct impact on patients and draw unwanted attention by regulatory bodies.

Since a new facility is under severe scrutiny by company executives, these undesirable outcomes
can be very difficult to explain to management.

Outsourcing microbial identifications

Given the extent of the QC microbiologist’s job functions and importance, as well as the
importance of microbial identifications to the cleanroom’s performance qualification,
outsourcing identifications is a logical and beneficial option. Most commercial systems have
limited throughput and cannot identify that large of a volume of microorganisms in a reasonable
amount of time. All the data then must be compiled into a report and analyzed, which takes even
more time and labor by the micro lab. Every day that it takes to complete the performance
qualification means thousands of dollars in lost revenue.

The new Annex 1 draft also emphasizes the use of “scientifically sound and modern methods.”
This applies also to microbial identifications. Phenotypic systems that identify organisms based
on biochemical and metabolic properties have been around for decades. The libraries associated
with these systems are often limited and focused on clinical isolates. The identification rates can
be subpar, and the number of retests requires more time, resources and cost. Identifications with
phenotypic systems are less accurate and reproducible, especially as manufacturing isolates are
stressed from the nutrient-poor environment and biochemical characteristics may not be
expressed.

On the other hand, modern identification methods include genotypic DNA sequencing and
proteotypic identifications using a MALDI-TOF mass spectrometer. DNA sequencing remains
the “gold standard” for identifications, but typically requires more labor, more equipment, and
technical expertise. Proteotypic identification methods do not offer phylogenetic information but
are fast and reproducible. The MALDI-TOF instrument is a significant investment, so many
companies choose to outsource both DNA sequencing as well as MALDI-TOF identifications.
Considering that the importance of accurate and reliable microbial identifications is clearly
emphasized for cleanroom qualifications in the Annex 1 draft, the optimal identification method
is DNA sequencing.

When selecting an outsourcing lab partner, consider the availability of tracking and trending data
tools. As mentioned in the previous section, Annex 1 expects frequent trending of environmental
monitoring samples. Having trending organism reports included with the identification service
could save significant time and reduce the risk of transcription errors. Thus, improving your data
integrity position, and strengthening your compliance position. The trending reports can give a
complete breakdown of what microorganisms were recovered from your cleanroom, allows you
to easily view changes from your baseline, and assess remediation efforts.

Outsourcing your microbial identifications to a reputable company using robust and accurate
services can give you confidence in your performance qualification. It can also speed up your
timeline, allow you to make informed decisions about your process and contamination controls,
decrease contamination risk, and save precious time and resources.

Another critical factor in selecting an outsourcing partner for microbial identifications should be
appropriate lab accreditations such as ISO 17025. This accreditation certifies the technical
competence of laboratories to perform specific tasks and guarantees that the results are obtained
according to valid methods and procedures that comply with precise standards.

Worth the investment

The revised Annex 1 guideline places renewed emphasis on facilities and contamination control.
This directly impacts cleanroom qualifications, which play a critical role in assessing the
manufacturing state of control and establishing a baseline for assessing changes and risk to the
final product. Accurate and reproducible microbial identifications in combination with
meaningful tracking and trending of the generated results are necessary for effective
contamination control and outsourcing these identifications can be beneficial.

Cleanroom qualifications are a huge investment of a company’s money, time and resources. A
strong and comprehensive qualification increases the company’s regulatory compliance position,
enhances product quality, and ensures patient safety.

References
1. ISO 14644-1:2015, “Cleanrooms and associated controlled environments — Part 1.”
2. Luke Christou, “The high cost of contamination in drug manufacturing,” Pharmaceutical
Technology, Sept. 12, 2018.
3. FDA Warning Letter, March 20, 2019.
4. Damon Larkin, “The contamination risk posed by laundered cleanroom apparel,” Kimberly-
Clark Professional, November 2014.
5. Edward Tidswell, “The cost of microbial control,” PDA Letter, Aug. 8, 2017.
6. David Westman, “Cost and Impact of a bioburden incident,” GE Healthcare Life Sciences
April 12, 2017.
Cleanroom Validation – Basic
Principles
POSTED ON MAY 22, 2018 BY BLUE THUNDER TECHNOLOGIES

22
May
Cleanrooms are expensive to build and maintain because they must be customized
to produce a specific product that is subject to special requirements that have been
established to minimize contamination.

When building or extending a cleanroom, it is crucial to design it right from the

outset to ensure that all requirements are met initially. Changes after the fact can
be very costly.

Cleanroom Design Considerations

Highly regulated environments like those found in the manufacture of medical
devices as well as the pharmaceutical industry, and the manufacture of PCBs,
require assurance that critical processes can be performed within controlled
conditions that have been validated.

In order to validate a cleanroom environment it is necessary to demonstrate

that:

1. air supplied to the cleanroom is of sufficient quantity to dilute or remove

contamination generated within the cleanroom,
2. air supplied to the cleanroom is of a quality that will not add to the
contamination levels in the cleanroom,
3. air moves in the direction from clean to less clean areas,
4. air movement within the cleanroom shows that there are no areas with
the room with high concentrations of contamination, and
5. manufacturing processes can be done in an environment that meets its
microbial contamination levels.

Cleanroom Validation Life Cycle

The process of designing, building, and validation testing and certification of a
cleanroom consists of five phases. They are:

1. Design qualification,
2. Installation qualification,
3. Operation qualification,
4. Performance qualification, and
5. Cleanroom certification.
Each phase is consistent with implementing, designing, and testing to specific
requirements. Methods for evaluation and measurements for Certification are
specified in ISO 14644-3. It calls for the following ten tests:

1. Airborne particle count test

2. Airflow test
3. Air pressure differential test
 4. Filter leakage test
5. Flow visualization test
6. Airflow direction test
7. Temperature test
8. Humidity test
9. Recovery test
10.Containment leak test
Cleanrooms are validated to a required class of cleanliness that is driven by user
requirements as defined in ISO 1464-1. Once certified to a particular class, the
cleanroom factors need to be monitored to ensure that parameters have not
changed or drifted, and that the environment is under control. A constant
monitoring program is mandated after certification. Compliance requirements are
specified in ISO 14644-2.

Cleanroom validation is more than simply counting particles. It includes numerous

different tests that must be performed in various cleanroom states in order to
verify that the cleanroom is fit for its intended use and meets the stipulations set
forth for the classification requirements governing the cleanroom application.

The information supplied in this article is for guidance only. Not all cleanrooms will use
the same procedures. Follow your specific cleanroom or company procedural manual
before this guide.

Cleanroom commissioning and qualification are critical processes that ensure the integrity and
functionality of controlled environments. These processes involve thorough planning, testing, and
documentation to verify that a cleanroom meets the required standards and regulations.

Table of Contents
 Importance of Cleanroom Commissioning and Qualification: Essential for several reasons:
 Cleanroom Basics:
 Cleanroom Commissioning Process
o Installation Qualification (IQ):
o Operational Qualification (OQ):
o Performance Qualification (PQ):
 Cleanroom Qualification
 Challenges and Considerations:
This article explores the definition, importance, and key components of cleanroom commissioning
and qualification. It also delves into the commissioning process, qualification parameters,
documentation requirements, challenges, and considerations.
By understanding these aspects, organizations can ensure the
optimal performance and reliability of their cleanroom
facilities.

Importance of Cleanroom Commissioning

and Qualification: Essential for several
reasons:
1. Compliance: Commissioning and qualification ensure compliance with regulatory
requirements, industry standards, and guidelines, such as ISO, GMP, and IEC.
2. Risk Mitigation: Thorough testing and verification processes help identify and mitigate
potential risks that could compromise the cleanroom’s integrity and performance.
3. Quality Assurance: Commissioning and qualification processes guarantee the quality,
reliability, and consistency of the cleanroom, reducing the likelihood of contamination and
product defects.
4. Operational Efficiency: By validating the cleanroom’s performance, commissioning and
qualification contribute to improved operational efficiency, optimized workflows, and
enhanced productivity.

Cleanroom Basics:
Cleanrooms are controlled environments designed to minimize the presence of airborne particles,
contaminants, and other variables that could affect sensitive processes or products. They are utilized
in industries such as pharmaceuticals, biotechnology, electronics, healthcare, and research
laboratories.

Classification of Cleanrooms: Cleanrooms are classified based on their particulate cleanliness

levels. Classification systems, such as ISO 14644-1, categorize cleanrooms into different classes,
ranging from ISO Class 1 (highest cleanliness) to ISO Class 9 (lowest cleanliness).

Key Components of a Cleanroom: Cleanrooms consist of several key components, including air
filtration systems, HVAC (heating, ventilation, and air conditioning) systems, controlled access
points, growing areas, and monitoring and control systems.
Cleanroom Standards and Regulations: Cleanrooms adhere to various standards and regulations
depending on the industry and application. Common standards include ISO 14644 for cleanliness,
GMP guidelines for pharmaceutical and healthcare industries, and IEC standards for electronics and
semiconductor industries.

Cleanroom Commissioning Process

Image Source: Researchgate.net
 1. Project Planning and Documentation: This involves defining project objectives, scope, and
requirements, as well as preparing detailed plans, specifications, and protocols for
commissioning and qualification.
2. Design Review: A comprehensive review of the cleanroom design ensures that it aligns with
the intended purpose and meets regulatory and industry standards.
3. Factory Acceptance Testing (FAT): FAT involves inspecting and testing cleanroom
components and equipment at the manufacturer’s site to ensure they meet the specified
requirements.
Installation Qualification (IQ):

Image Source: cytivalifesciences

Installation qualification(IQ) refers to the process of verifying that an instrument or item of

equipment has been delivered, installed and configured in accordance with a manufacturer’s standard
or an approved installation checklist.

Equipment Installation Verification: This step verifies that all cleanroom equipment, instruments,
and systems are installed correctly and in accordance with the design specifications.
Documentation Review: The review of installation records, equipment manuals, and other relevant
documents ensures proper documentation of the installation process.
Operational Qualification
In OQ, the purpose is to ensure equipment performance matches the user requirements specification
within the operating ranges specified by the manufacturer. It involves identifying and inspecting
equipment features that can have an impact on the quality of the final product.

Performance Testing: OQ involves performance testing of cleanroom equipment, HVAC systems,

filtration systems, and other critical components to ensure they meet the specified performance
criteria.
Risk Assessment: A risk assessment helps identify potential vulnerabilities and risks associated with
cleanroom operations, allowing for the implementation of appropriate mitigation measures.
Performance Qualification (PQ):
The Performance Qualification is a validation protocol that demonstrates that equipment or systems
can perform or control processes in accordance with written and pre-approved specifications while
operating in the environment specified for them.
Validation Testing: PQ involves conducting extensive testing to validate the cleanroom’s
performance under normal operating conditions, including particle counts, air change rates,
temperature and humidity control, and pressure differentials.
Data Analysis and Reporting: The collected data is analyzed and compared against the predefined
acceptance criteria. A comprehensive report is generated to document the qualification process,
results, and any deviations or non-conformities.

Cleanroom Qualification
Qualification of cleanrooms is defined as “the process of evaluating a classified cleanroom’s level of
compliance with its intended use.” Thus, qualification involves classification.
Airflow and Air Change Rates: Proper airflow patterns and sufficient air change rates are essential
for controlling particle levels and maintaining the cleanliness of a cleanroom. Qualification ensures
that the airflow systems meet the specified requirements and maintain the desired particle counts
within the cleanroom.
Temperature and Humidity Control: Qualification verifies the effectiveness of the cleanroom’s
HVAC systems in maintaining precise temperature and humidity levels within the specified range to
meet the operational requirements.
Particle Monitoring and Control: Qualification involves the evaluation of particle monitoring
systems and procedures to ensure accurate and reliable measurement of airborne particle
concentrations. It also assesses the effectiveness of cleanroom practices and protocols for minimizing
particle generation and contamination.
Cleanroom Pressurization: Pressurization plays a crucial role in preventing the ingress of
contaminants into the cleanroom. Qualification verifies the positive or negative pressure differentials
between adjacent areas, ensuring that the desired pressure relationships are maintained.
Contamination Control Measures: Qualification assesses the effectiveness of contamination
control measures such as gowning procedures, equipment sanitization, material transfer protocols,
and cleaning and disinfection processes to minimize the risk of contamination within the cleanroom.
Documentation and Reporting: A. Validation Plan and Protocol Development: A well-defined
validation plan and protocols outline the approach, methods, acceptance criteria, and test procedures
to be followed during the cleanroom commissioning and qualification process.
Data Collection and Analysis: Accurate and comprehensive data collection during testing and
qualification is crucial. Data analysis helps determine compliance with specified requirements and
identifies areas that may require corrective actions.
Non-Conformance and Deviation Handling: Any non-conformance or deviation observed during
commissioning and qualification should be documented, investigated, and addressed through
appropriate corrective and preventive actions.
Final Qualification Report: A final qualification report summarizes the entire commissioning and
qualification process, including the objectives, activities, test results, deviations, and corrective
actions taken. It serves as a reference for ongoing maintenance, compliance, and future audits.

Challenges and Considerations:

Common Challenges in Cleanroom Commissioning and Qualification: Common challenges
include design flaws, inadequate project planning, equipment malfunction, non-compliance with
regulations, lack of qualified personnel, and unforeseen technical issues. These challenges can impact
the efficiency and effectiveness of the commissioning and qualification process, necessitating careful
planning and mitigation strategies.
Conclusion:
Cleanroom commissioning and qualification are vital processes for ensuring the reliability,
compliance, and performance of controlled environments. By following established protocols,
adhering to standards and regulations, and addressing potential challenges, organizations can achieve
cleanroom facilities that meet stringent requirements and support their critical operations.

How to validate your cleanroom? HVAC

performance qualification basics
Published: 21-Sep-2021Featured companies:Lighthouse Worldwide Solutions

Design & Build HVAC Regulatory

HVAC performance qualification roadmap, application guidance and tips as per ISO
14644-3:2019; cleanroom test methods and cleanroom classification as per ISO 14644-
1:2015
Cleanroom HVAC performance qualification, known as “cleanroom validation”, is the most
important set of tests to make sure that the cleanroom is ready for its intended use and can meet
and exceed user requirements that are mentioned at a very early stage of a cleanroom built.

What are the tests we should perform for cleanroom classification as part of our “cleanroom validation”?

Cleanroom airborne particle count and classification is the only way to classify cleanroom.
Classification is the method of assessing the level of cleanliness against a specification for a
cleanroom or clean zone. ISO14644-1 is the only reference to assess cleanliness level (as ISO
Class N) and there are no other tests to perform to classify cleanroom. Table 1 should be your
reference for “ISO Classes of air cleanliness by particle concentration”

The number of sampling locations used to be calculated in the 1999 edition but the latest version
giving us a table to check and define no. of sampling locations related to the cleanroom area.
What are the other tests we should perform as part of HVAC performance qualification?

In order to perform proper cleanroom performance qualification, there are several “supportive
tests” that are mentioned in ISO 14644-3:2019 “Cleanroom Test Methods” previously known as
“optional tests” in the 2005 version of this ISO 14644-3 standard. All these supportive tests are
captured at ISO 14644-3:2015 Table 2. Each supporting tests are listed with principles (section
4), procedures (Annex B), and Apparatus (Annex C).
Even these tests are known as “supportive/optional” tests,
for a proper cleanroom validation, you should perform the
most suitable ones as per your requirement. Reason here is,
ISO 14644 series are for all industries that are using
cleanrooms and controlled environments. For example,
electrostatic tests are critical for semiconductor and micro-
electronics industry but not for automotive paint shops with
controlled environments. Or airflow visualisation is a key
parameter for unidirectional airflow verification at sterile
production lines in pharmaceutical industries while it is not
critical for medical packaging cleanroom with a turbulent
air. C
Cleanroom commissioning and qualification are critical processes that ensure the integrity and
functionality of controlled environments. These processes involve thorough planning, testing, and
documentation to verify that a cleanroom meets the required standards and regulations.

Table of Contents
 Importance of Cleanroom Commissioning and Qualification: Essential for several reasons:
 Cleanroom Basics:
 Cleanroom Commissioning Process
o Installation Qualification (IQ):
o Operational Qualification (OQ):
o Performance Qualification (PQ):
 Cleanroom Qualification
 Challenges and Considerations:
This article explores the definition, importance, and key components of cleanroom commissioning
and qualification. It also delves into the commissioning process, qualification parameters,
documentation requirements, challenges, and considerations.

By understanding these aspects, organizations can ensure the

optimal performance and reliability of their cleanroom
facilities.

Importance of Cleanroom Commissioning

and Qualification: Essential for several
reasons:
 1. Compliance: Commissioning and qualification ensure compliance with regulatory
requirements, industry standards, and guidelines, such as ISO, GMP, and IEC.
2. Risk Mitigation: Thorough testing and verification processes help identify and mitigate
potential risks that could compromise the cleanroom’s integrity and performance.
3. Quality Assurance: Commissioning and qualification processes guarantee the quality,
reliability, and consistency of the cleanroom, reducing the likelihood of contamination and
product defects.
4. Operational Efficiency: By validating the cleanroom’s performance, commissioning and
qualification contribute to improved operational efficiency, optimized workflows, and
enhanced productivity.

Cleanroom Basics:
Cleanrooms are controlled environments designed to minimize the presence of airborne particles,
contaminants, and other variables that could affect sensitive processes or products. They are utilized
in industries such as pharmaceuticals, biotechnology, electronics, healthcare, and research
laboratories.

Classification of Cleanrooms: Cleanrooms are classified based on their particulate cleanliness

levels. Classification systems, such as ISO 14644-1, categorize cleanrooms into different classes,
ranging from ISO Class 1 (highest cleanliness) to ISO Class 9 (lowest cleanliness).

Key Components of a Cleanroom: Cleanrooms consist of several key components, including air
filtration systems, HVAC (heating, ventilation, and air conditioning) systems, controlled access
points, growing areas, and monitoring and control systems.
Cleanroom Standards and Regulations: Cleanrooms adhere to various standards and regulations
depending on the industry and application. Common standards include ISO 14644 for cleanliness,
GMP guidelines for pharmaceutical and healthcare industries, and IEC standards for electronics and
semiconductor industries.

Cleanroom Commissioning Process

Image Source: Researchgate.net
1. Project Planning and Documentation: This involves defining project objectives, scope, and
requirements, as well as preparing detailed plans, specifications, and protocols for
commissioning and qualification.
2. Design Review: A comprehensive review of the cleanroom design ensures that it aligns with
the intended purpose and meets regulatory and industry standards.
3. Factory Acceptance Testing (FAT): FAT involves inspecting and testing cleanroom
components and equipment at the manufacturer’s site to ensure they meet the specified
requirements.
Installation Qualification (IQ):
Image Source: cytivalifesciences
Installation qualification(IQ) refers to the process of verifying that an instrument or item of
equipment has been delivered, installed and configured in accordance with a manufacturer’s standard
or an approved installation checklist.

Equipment Installation Verification: This step verifies that all cleanroom equipment, instruments,
and systems are installed correctly and in accordance with the design specifications.
Documentation Review: The review of installation records, equipment manuals, and other relevant
documents ensures proper documentation of the installation process.
Operational Qualification (OQ):

In OQ, the purpose is to ensure equipment performance matches the user requirements specification
within the operating ranges specified by the manufacturer. It involves identifying and inspecting
equipment features that can have an impact on the quality of the final product.

Performance Testing: OQ involves performance testing of cleanroom equipment, HVAC systems,

filtration systems, and other critical components to ensure they meet the specified performance
criteria.
Risk Assessment: A risk assessment helps identify potential vulnerabilities and risks associated with
cleanroom operations, allowing for the implementation of appropriate mitigation measures.
Performance Qualification (PQ):
The Performance Qualification is a validation protocol that demonstrates that equipment or systems
can perform or control processes in accordance with written and pre-approved specifications while
operating in the environment specified for them.
Validation Testing: PQ involves conducting extensive testing to validate the cleanroom’s
performance under normal operating conditions, including particle counts, air change rates,
temperature and humidity control, and pressure differentials.
Data Analysis and Reporting: The collected data is analyzed and compared against the predefined
acceptance criteria. A comprehensive report is generated to document the qualification process,
results, and any deviations or non-conformities.

Cleanroom Qualification
Qualification of cleanrooms is defined as “the process of evaluating a classified cleanroom’s level of
compliance with its intended use.” Thus, qualification involves classification.

Airflow and Air Change Rates: Proper airflow patterns and sufficient air change rates are essential
for controlling particle levels and maintaining the cleanliness of a cleanroom. Qualification ensures
that the airflow systems meet the specified requirements and maintain the desired particle counts
within the cleanroom.
Temperature and Humidity Control: Qualification verifies the effectiveness of the cleanroom’s
HVAC systems in maintaining precise temperature and humidity levels within the specified range to
meet the operational requirements.
Particle Monitoring and Control: Qualification involves the evaluation of particle monitoring
systems and procedures to ensure accurate and reliable measurement of airborne particle
concentrations. It also assesses the effectiveness of cleanroom practices and protocols for minimizing
particle generation and contamination.
Cleanroom Pressurization: Pressurization plays a crucial role in preventing the ingress of
contaminants into the cleanroom. Qualification verifies the positive or negative pressure differentials
between adjacent areas, ensuring that the desired pressure relationships are maintained.
Contamination Control Measures: Qualification assesses the effectiveness of contamination
control measures such as gowning procedures, equipment sanitization, material transfer protocols,
and cleaning and disinfection processes to minimize the risk of contamination within the cleanroom.
Documentation and Reporting: A. Validation Plan and Protocol Development: A well-defined
validation plan and protocols outline the approach, methods, acceptance criteria, and test procedures
to be followed during the cleanroom commissioning and qualification process.
Data Collection and Analysis: Accurate and comprehensive data collection during testing and
qualification is crucial. Data analysis helps determine compliance with specified requirements and
identifies areas that may require corrective actions.
Non-Conformance and Deviation Handling: Any non-conformance or deviation observed during
commissioning and qualification should be documented, investigated, and addressed through
appropriate corrective and preventive actions.
Final Qualification Report: A final qualification report summarizes the entire commissioning and
qualification process, including the objectives, activities, test results, deviations, and corrective
actions taken. It serves as a reference for ongoing maintenance, compliance, and future audits.

Challenges and Considerations:

Common Challenges in Cleanroom Commissioning and Qualification: Common challenges
include design flaws, inadequate project planning, equipment malfunction, non-compliance with
regulations, lack of qualified personnel, and unforeseen technical issues. These challenges can impact
the efficiency and effectiveness of the commissioning and qualification process, necessitating careful
planning and mitigation strategies.
Conclusion:
Cleanroom commissioning and qualification are vital processes for ensuring the reliability,
compliance, and performance of controlled environments. By following established protocols,
adhering to standards and regulations, and addressing potential challenges, organizations can achieve
cleanroom facilities that meet stringent requirements and support their critical operations.

To learn more about planning, implementation and a proper reporting for cleanroom
qualifications, please sign up to our knowledge centre.
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Home / Learning center / Clean Room Classifications (ISO 8, ISO 7, ISO 6, ISO
5)
CLEAN ROOM
CLASSIFICATIONS
(ISO 8, ISO 7, ISO 6, ISO 5)
CLEAN ROOM CLASSIFICATIONS
Clean rooms are classified according to the cleanliness level of the air inside the controlled
environment. The clean room class is the level of cleanliness the room complies with, according
to the quantity and size of particles per cubic meters of air. The primary authority in the US and
Canada is the ISO classification system ISO 14644-1.
This ISO standard includes these clean room classes : ISO 1, ISO 2, ISO 3, ISO 4, ISO 5, ISO 6,
ISO 7, ISO 8 and ISO 9. ISO 1 is the “cleanest” class and ISO 9 is the “dirtiest” class. Even if
it’s classified as the “dirtiest” class, the ISO 9 clean room environment is cleaner than a regular
room.
The most common ISO clean room classes are ISO 7 and ISO 8. The Federal Standard 209 ( FS
209E ) equivalent for these ISO classes are Class 10,000 and Class 100 000.
The old Federal Standard 209E ( FS 209E ) includes these clean room classes : Class 100,000;
Class 10,000; Class 1,000; Class 100; Class 10; Class 1. This standard was replaced in 1999 by
ISO-14644-1. It was withdrawn in 2001, but it is still widely used.
Clean rooms must also follow industry-specific and international standards. For example, EU
GMP (A-B-C-D), applies to pharmaceutical products and USP (795, 797 and 800) to
compounding pharmacies.
You might also like this article —>How Classification Impacts your Cleanroom Design
Want to learn more about Clean Rooms? —>What is a Clean room?
REQUEST A QUOTE
DOWNLOAD OUR PDF CLEANROOM BROCHURE

ISO CLEANROOM STANDARDS

AND LAYOUTS
Depending on the class of clean room system you would like to reach, it is important to allow for
enough square footage. This is critical not just for the clean zone, but also for the
airlocks/gowning room which prevent the migration of particles from outside into the clean
space.
The rule of thumb is that you should not skip over more than one class when you move towards a
cleaner room (for example, from ISO 7 to ISO 6, not from ISO 8 to ISO 6), as illustrated below.
In reality, however, you can reach a cleaner class with fewer airlocks than described below with
the appropriate air changes per hour.
This depends on the process taking place inside the cleanroom, the size of the cleanroom, the
number of people working inside, the equipment inside, etc. Seek the help of a cleanroom expert
who can create the optimal layout for your particular needs.
Already in the design process of your cleanroom? Download our Cleanroom Checklist to give
a jump start to your cleanroom project!
DOWNLOAD OUR PDF CLEANROOM CHECKLIST

ISO 8 CLEANROOM (CLASS 100,000 CLEANROOM)

Let’s assume that an unclassified space (office or lab) is ISO 9. In this case, you can directly
enter an ISO 8 cleanroom, without an airlock. Depending on the production process inside the
cleanroom, however, you may have to add a gowning room.
 ISO 8 zone | 15–25 air changes per hour
Non-unidirectional air flow
Some of our ISO 8 Cleanroom past projects :
ISO 8 cleanroom for Pharmaceutical Manufacturing
Cleanroom for Pharmaceutical Industry
Cleanroom wall addition for Medtech Manufacturer
ISO 8 cleanroom for Medical Device Manufacturing
ISO 8 cleanroom for the Automotive Industry
ISO 7 CLEANROOM (CLASS 10000 CLEAN ROOM)
This is one of the most common classes of cleanrooms. If you need an ISO 7 cleanroom, you
should consider having an ISO 8 airlock/gowning room prior to entering the ISO 7 room. The air
changes per hour will vary in both rooms as described below.
 ISO 7 zone | 30–60 air changes per hour
 ISO 8 zone | 15–25 air changes per hour (ante-room)
Non-unidirectional air flow
Some of our ISO 7 Cleanroom past projects :
Clinical Manufacturing Facility for Cell and Gene Therapy – CGMP cleanroom
ISO 7 cleanroom for Electronic Component Production
ISO 7 cleanroom for Nutraceutical Industry
Clinical Trials – Drug Development cleanroom
ISO 7 sterile compounding non-hazardous facility
In-Hospital compounding cleanroom – ISO 7 ( USP-797 )
ISO 6 CLEANROOM (CLASS 1,000 CLEANROOM)
In theory, for an entire room to reach ISO 6 air cleanliness, you need to enter the cleanroom via
an ISO 8 (ante-room), then go through an ISO 7, to finally get into the ISO 6, as shown in the
image.
In reality however, you can reach an ISO 6 cleanroom with 1 (recommendation is 2) airlock.
Again, it depends of the size of the room, the process taking place inside the cleanroom, the
number of people working inside, the equipment inside, etc.
Unidirectional air flow is sometimes recommended to reach ISO 6 classification. For a room of
less than 4–6 meters in width (depending on the activities taking place inside the cleanroom), air
returns can be positioned on the side of the walls instead of in the floor. Installing air returns in
the floor is more expensive.
 ISO 6 zone | 90–180 air changes per hour
 ISO 7 zone | 30–60 air changes per hour
 ISO 8 zone | 15–25 air changes per hour (ante-room)
Some of our ISO 6 Cleanroom past projects :
ISO 6 cleanroom for semiconductor
Cleanroom for electronics manufacturing services ( ISO 6 )
ISO 6 Cell Production cleanroom for animal laboratory
ISO 5 CLEANROOM (CLASS 100 CLEANROOM)
In theory, for a classified room (not just below a LAFW hood) to reach ISO class 5 air
cleanliness, you need to enter the cleanroom via an ISO 8 (ante-room), then go through an ISO 7,
followed by an ISO 6 to finally get into the ISO class 5 cleanroom.
In reality, however, you can reach an ISO 5 cleanroom with 2 or 3 airlocks. The optimal layout
depends on the process taking place inside the cleanroom, the size of the room, the number of
people working inside, the equipment inside, etc.
In addition, an ISO 5 or class 100 clean room needs to use unidirectional air flow.
Unidirectional air flow cleanrooms use much more air than non-directional air flow cleanrooms.
High efficiency filters are installed across the entire ceiling.
The filtered air sweeps down the room in a unidirectional way, at a velocity generally between
0.3 m/s and 0.5 m/s, and exits through the floor, removing the airborne contamination from the
room. Cleanrooms using unidirectional air flow are more expensive than non-unidirectional
ones, but can comply with more stringent classifications, such as ISO 5 or lower.
 ISO 5 zone | 240–360 air changes per hour
 ISO 6 zone | 90–180 air changes per hour
 ISO 7 zone | 30–60 air changes per hour
 ISO 8 zone | 15–25 air changes per hour (ante-room)
Some of our ISO 5 Cleanroom past projects :
ISO 5 Nanofabrication cleanroom facility
ISO 14644-1 FS 209E

ISO 3 Class 1

ISO 4 Class 10
 ISO 5 Class 100

ISO 6 Class 1,000

ISO 7 Class 10,000

ISO 8 Class 100,000

MPARISON BETWEEN SELECTED EQUIVALENT OF FS 209E ( FED STD-209E ) A

ISO 14644-1
CLEAN ROOM CLASSIFICATION PARTICLE
CONCENTRATION
The basis of clean room standards is the micrometer, or micron for short (µm), which is the size
of the particles to be filtered. As stated before, clean rooms are classified by how clean the air is,
according to the number of particles and size of particles per volume of air. The clean room
classification table below shows the maximum concentration limits (particles/m3 of air) for
particles equal to and larger than the considered sizes shown.
Some classifications do not require certain particle sizes to be tested because the respective
concentrations are too low or too high to be tested, but they should not be zero.

Maximum Particles/m3 Particles/ft3

1µm ≥0.2µm ≥0.3µm ≥0.5µm ≥1µm ≥5µm ≥0.5µm

10

00 24 10

000 237 102 35 1

,000 2,370 1,020 352 83 10

0,000 23,700 10,200 3,520 832 29 100

237,00
0,000 102,000 35,200 8,320 293 1,000
0

352,000 83,200 2,930 10,000

3,520,000 832,000 29,300 100,000

 35,200,000 8,320,000 293,000

ISO CLEAN ROOM STANDARDS AND THE FS 209E EQUIVALENT

** Old FS 209E classes were calculated in particles per cubic foot, whereas ISO classes are in
cubic meter of air.
Maximum Particles/m3 Particles/ft3

≥0.3µ
.1µm ≥0.2µm ≥0.5µm ≥1µm ≥5µm ≥0.5µm
m

352,000 83,200 2,930 10,000

OW TO READ THE CLEAN ROOM CLASSIFICATION PARTICLE COUNT GRAP

For ISO 7, particles smaller than 0.5 microns (≥0.1 µm, ≥0.2 µm, ≥0.3 µm) are not taken into
consideration. The concentration of particles of ≥0.5 µm and above should be below 352,000, for
particles of 1 micron and above 83,200 or lower and for particles of 5 microns and above 2,930
or lower.

CLEANROOM CLASSIFICATION AND AIR CHANGES PER

HOUR
Air cleanliness is achieved by passing the air through HEPA filters using flow principles such as
laminar flow. The more often the air passes through the HEPA filters, the fewer particles are left
in the room air. The volume of air filtered in one hour divided by the volume of the room gives
the number of air changes per hour.
ISO Class Average number of air changes per hour

ISO 5 240–360 (unidirectional air flow)

ISO 6 90–180

ISO 7 30–60

ISO 8 10–25

Conventional building 2–4

THE NUMBER OF AIR CHANGES PER HOUR ACCORDING TO THE ISO CLASS
The above-suggested air changes per hour are only a design rule of thumb. They should be
computed by an HVAC clean room expert, as many aspects must be taken into consideration,
such as the size of the room, the number of people in the room, the equipment in the room, the
processes involved, the heat gain, etc.
CONTACT OUR EXPERTS TO DISCUSS YOUR PROJECT
Disclaimer
This article will help you understand the basic differences between an ISO 5, ISO 6, ISO 7 and
ISO 8 clean room as per ISO 14644. Please note that this information is only provided for
educational purposes.
The definitions in this article are oversimplified in order to assist with understanding. This
article will not help you decide which clean room classification you must reach. If help is needed
in this respect, seek the advice of an expert in your industry (pharmaceutical, medical devices,
sterile compounding, electronics, etc.).

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PARTNERSHIPS
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CLEANROOM VALIDATION, HEATING VENTILATION AND AIR
CONDITIONING SYSTEM HVAC, VALIDATION ENGINEERING

HOW TO PERFORM A
CLEANROOM VALIDATION AS
PER ISO14644
 Author: Ramon Cayuela
 Published Date: October 10, 2020
 Make a Cleanroom Validation in compliance with ISO14644

The validation of the cleanroom shall demonstrate that the production area (in which your products and components shall be exposed to the
environment during its manufacturing process) is suitable and appropriate under acceptable conditions and parameters of the design in
compliance with the international organization ISO under standard ISO14644.

The cleanroom validation protocol may include the following (14) challenges and testing activities:
 1. Room Temperature
2. % Relative Humidity
3. Viable particulate – surface
4. Viable particulate air
5. Non-Viable particulate
6. Pressure Differential
7. HEPA Filter Integrity
8. HEPA Filters Velocities
9. Room Air Changes
10. Room Air Balance CFMs
11. Smoke Test – Airflow pattern
12. Particle Decontamination Test
13. Recovery Test – AHU shut down
14. Sound and Lighting Test
Additional criteria to be considered which affects room cleanliness should include:
 building finishes and structure
 air filtration
 location of air terminals and directional airflow
 material flow
 personnel flow
 gowning procedures
 equipment movement
 the process is carried out (open or closed system)
 outside air conditions
 occupancy
 type of product
 cleaning standard operating procedures (SOPs).
When is required an HVAC System and Cleanroom validation?
The HVAC and cleanroom validation is performed every time an Environmental Control Area (ECA) is required and used for GMP
manufacturing purposes.

In case that an ECA is used for the cGMP manufacturing process, the HVAC and cleanroom validation is a mandatory requirement of each
environmental controlled area as established by the Federal Register, section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)).

It will guarantee that all necessary environmental conditions shall be available for the intended use.

The cleanroom validation must be performed after completed the facility and HVAC qualification of all equipment installation and machinery
connections, supplies, air conditioning, water system, compresses air system, electric power capacity, city water, etc. with their respective
commissioning, IQ’s, OQ’s and PQ’s

Typically, the HVAC validation refers and consider the commissioning or qualification of all utilities and room related to each product
manufacturing operation.

What testing is required in the Cleanroom Validation?

The most common testing performed during a cleanroom validation are:
Airflow or smoke pattern
For the evaluation of this parameter, a smoke generation device is used to add a visible fume in front of the HEPA Filters or in the area in
which the product shall be exposed. The distribution of smoke is observed, documented, and recorded. It should be uniform following a
laminar flow pattern in the exit direction to return ducts without any major turbulence.

Airflow velocity and changes per hour

For this test, the area of HVAC is divided into hypothetical grids and the air velocity is measured at each grid and then the average air velocity
(V) is calculated. The area of the HEPA filter inlet (A) is calculated in feet and the total air volume (T) is then calculated by multiplying the
average velocity of the air and the area of the inlet (T = A × V). After this, the volume of the room is calculated and the air changes per hour are
obtained by dividing the total air change by the volume of the room.

Filter leak test

For the leak test of the HEPA filter, a velometer is placed at the front of the AHU system and the air velocity is checked. The air velocity
should be within the higher limit of the HEPA filter.

Particle count – nonviable particle test

A particle counter is used to conduct the test. Particle count is taken at static conditions before the operation as well as operational working
conditions. The particle count should be within the range as per the standards of particle classification, for example, ISO Class 7, etc.

Viable particle monitoring

Viable monitoring is performed on daily basis by employing the swab test and using nutrient agar medium for the incubation of
microorganisms. The different media plates are exposed in every manufacturing section. The microorganism count should be within the range
otherwise, an investigation must be initiated to evaluate the root cause, effective corrective and preventive actions

Filter integrity test

The HEPA filter integrity is tested by injecting particles of a predetermined size (0.2 um or greater) using an aerosol generator into the HEPA
filters to determine if they are retaining the aerosol particles. The 100% upward flow of the aerosol must be captured into the HEPA filter. A
receptor probe that detects the aerosol is used to determine if they are passing thru the HEPA filter or not. Each HEPA filter must be tested and
monitored periodically (e.g. annually or every two years). It is important to know if they are broken. Therefore, the amount of the aerosol
detected passing thru it is monitored and documented as part of the qualification. No residues or traces of aerosol must be detected after the
HEPA filter to pass the acceptance criteria of the filter integrity test.

Pressure difference
It is calculated by making use of the manometer attached to the walls of the adjacent area. The pressure difference is generally kept positive
from the cleanest area to the less clean area in the range from 1 and 20 mmHg pressure.

Recovery test
The recovery of temperature and humidity conditions is checked after losing operational power conditions or doors opening. For example, the
humidity and temperature are checked at the off position of the HVAC system. Then, the HVAC system is turn -on to verify how much time it
takes to recover the expected conditions, the time required to stabilize the temperature and humidity is noted. Also, this test can be done,
opening the doors during some predetermined amount of time, then document the amount of time it takes to reach the expected environmental
conditions.

Temperature and humidity uniformity test

The uniformity of temperature and humidity are monitored by employing a calibrated datalogger, chart recorder, thermocouples, thermometer,
RTD, manometer, etc. The two parameters are monitored in a continuous manner, documented in the format and stabilization is ensured within
the specified limit.

Fresh air determination

The fresh air intake is observed at the inlet on the fresh air damper. The total air change is calculated. The intake of fresh air is divided by the
total air change in the room and multiplied by 100 to obtain the percent fresh air intake on each cycle by the HVAC system in all the individual
rooms.

How determine or calculate the number of samples required to classify a cleanroom as per
ISO 14644: 2015?
The number of samples to be taken on each cleanroom depends on the area.

The ISO 14644 standard can be used to determine the sampling plan and the number of sampling points to use during the HVAC system
validation. The ISO standards are not free or public domain since it has copyrights. Refer to the following table as an example.

Area of cleanroom (m2) less than or equal to Minimum number of sampling locations to be tested (NL)

<1000 See ISO 14644-1 (2015) sampling ta1bles

1000 27

>1000 See formula A.1 in the ISO 14644-1 (2015)

For a complete table and more information about the iso 14644-1:2015, refer to httpss://www.iso.org/standard/53394.html
How to prepare a cleanroom validation protocol?
Some people perform the validation strategy following this approach:

Qualification Deliverables HVAC System

CleanRoom AHU Control System

IQ X X X

OQ X X X

PQ X X X

CSV Control System X

The cleanroom validation PQ protocol may include, but, is not limited to the following sections and information, (as applicable)

1. Purpose
2. Scope
3. General Definitions
4. Safety
5. Reference Documents
6. Responsibility
7. Exceptional Conditions and Discrepancies
8. Strategy: Environmental Monitoring Instructions
 Room Temperature And % Relative Humidity Monitoring
 Differential Pressure Monitoring
 Non-Viable Particulate Monitoring
 Viable Particulate Monitoring
 Air Flow Monitoring and Balancing
 Room Airflow Pattern Test – Smoke Test
 HEPA Filter Air Velocity Test
 HEPA Filter Integrity Test
 Particle Decontamination Test
 Recovery Test – Hvac System Shut-Down and Restore Test
 Room Air Changes Test
 Sound Pressure and Lighting Test
9. Product Disposition
10. Room/Area Certification Parameters Not Meeting Requirements
11. Documentation
12. Approvals

What is the ISO 14644?

The ISO 14644 is a group of several international standards dedicated to bringing the guidelines related to the ECA Environmental Controlled
Area management.

It establishes the classification of air cleanliness in terms of the concentration of airborne particles in cleanrooms and clean zones.

ISO 14644 Standards were first formed from the US Federal Standard 209E Airborne Particulate Cleanliness Classes in Cleanrooms and Clean
Zones.
The ISO 14644 is composed of the following documents:
 ISO 14644-1: Classification of air cleanliness
 ISO/DIS 14644-1.2(2014): Classification of air cleanliness by particle concentration
 ISO 14644-2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1
 ISO/DIS 14644-2.2(2014): Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle
concentration
 ISO 14644-3: Test Methods
 ISO 14644-4: Design, Construction, and Start-up
 ISO 14644-5: Operations
 ISO 14644-6: Vocabulary
 ISO 14644-7: Separative devices (clean air hoods, gloveboxes, isolators, and mini environments
 ISO 14644-8: Classification of airborne molecular contamination
  ISO 14644-9: Classification of surface particle cleanliness
 ISO 14644-10: Classification of Surface Cleanliness by Chemical Concentration
 ISO 14644-12: Classification of Air Cleanliness by Nanoscale Particle Concentration
For more information, refer to httpss://www.iso.org/standard/53394.html
For a preview, refer to httpss://www.iso.org/obp/ui/#iso:std:iso:14644:-1:ed-2:v1:en
What is the US FED 209D?
The FED-STD-209 E Airborne Particulate Cleanliness Classes in Cleanrooms and Clean zones was a federal standard concerning the
classification of air cleanliness, intended for use in environments like clean rooms. The standard-based its classifications on the measurement of
airborne particles.

The time before the ISO 14644 was implemented, this legacy document established the 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.

The standard was canceled on November 29, 2001, by the United States General Services Administration (GSA). The document was
superseded by standards written for the International Organization for Standardization (ISO).

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More details on specific FDA expectations for cleanroom validation can be found in the guidance document below.

httpss://www.iso.org/standard/53394.html
For a preview, refer to httpss://www.iso.org/obp/ui/#iso:std:iso:14644:-1:ed-2:v1:en
Three (3) options to create a qualification protocol for the cleanroom:
Option 1. You can create a great protocol, using a template.

You can download a free sample of a validation template in .pdf format.

To see the complete list of the most popular validation templates, click here.
In addition, you can request a quotation to buy online a full validation template document in MS Word format that is completely editable, ready
to fill, and adapt to your needs.
Option 2. We can bring you a formal training on how to create your own validation protocols using our
template(s).

This option is recommended if you want to learn more about how to build a robust validation protocol. One of our expert(s) will provide online
step-by-step training to your team (unlimited assistance) on how to build a reliable validation protocol using a template. You can improve your
corporate validation procedures and policies incorporating our template sections. It includes the template, an exam, and a training certificate for
each assistant. Request a quote now.
Option 3. We can create a customized qualification.

One of our expert(s) will create and prepare for you a customized validation protocol with the inputs and specific information of your company. It
may include, online support in document creation, execution, or final reporting, Request a quote online.
GET IN COMPLIANCE TODAY, CONTACT US (Hablamos Español)
STATUTORY AND REGULATORY REQUIREMENTS
for cleanroom validation
 Validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21
U.S.C. 351(a)(2)(B)), which states the following:

“… a drug (including a drug contained in a medicated feed) shall be deemed to be adulterated if the methods used in, or the facilities or controls
used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good
manufacturing practice to assure that such drug meets the requirement of the act as to the safety and has the identity and strength, and meets the
quality and purity characteristics, which it purports or is represented to possess.”
Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the
Act (21 U.S.C. 351(a)(2)(B)), which states the following:
FDA regulations describing current good manufacturing practice (CGMP) for finished pharmaceuticals are provided in 21 CFR parts 210 and 211.

The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process material and the finished product
meet predetermined quality requirements and do so consistently and reliably.

Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process
validation is provided in § 211.100(a), which states that “[t]here shall be written procedures for production and process control designed to assure
that the drug products have the identity, strength, quality, and purity they purport or are represented to possess…” (emphasis added). This
regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes.
Other CGMP regulations define the various aspects of validation. For example, § 211.110(a), Sampling and testing of in-process materials and
drug products, requires that control procedures “. . . be established to monitor the output and to validate the performance of those
manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product”
(emphasis added).

Under this regulation, even well-designed processes must include in-process control procedures to assure final product quality. In addition, the
CGMP regulations regarding sampling set forth a number of requirements for validation:

Samples must represent the batch under analysis (§ 211.160(b)(3)); the sampling plan must result in statistical confidence (§ 211.165(c) and (d));
and the batch must meet its predetermined specifications (§ 211.165(a)).

In addition to sampling requirements, the CGMP regulations also provide norms for establishing in-process specifications as an aspect of process
validation. Section 211.110(b) establishes two principles to follow when establishing in-process specifications. The first principle is that

“. . . in-process specifications for such characteristics [of in-process material and the drug product] shall be consistent with drug product final
specifications . . . .”

Accordingly, in-process material should be controlled to assure that the final drug product will meet its quality requirements. The second principle
in this regulation further requires that in-process specifications “. . . shall be derived from previous acceptable process average and process
variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.”

This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability.

The CGMP regulations also describe and define activities connected with process design, development, and maintenance. Section 211.180(e)
requires that information and data about product quality and manufacturing experience be periodically reviewed to determine whether any changes
to the established process are warranted. Ongoing feedback about product quality and process performance is an essential feature of process
maintenance.

In addition, the CGMP regulations require that facilities in which drugs are manufactured be of suitable size, construction, and location to facilitate
proper operations (§ 211.42). Equipment must be of appropriate design, adequate size, and suitably located to facilitate operations for its intended
use (§ 211.63). Automated, mechanical, and electronic equipment must be calibrated, inspected, or checked according to a written program
 designed to assure proper performance (§ 211.68).

References
httpss://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=225.1
https://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf
httpss://www.fda.gov/media/94074/download
httpss://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=225.1
httpss://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-records-electronic-signatures-scope-and-
application
httpss://ispe.org/publications/guidance-documents/gamp-5
Related topics and resources:
Validation Plan, Installation Qualification, Operational Qualification, Performance Qualifications, Component Qualification, Traceability Matrix,
Ppk, Control Charts, Cpk, User Requirements, Functional Requirement Specifications, GAMP5, risk assessment

Ramon Cayuela, MS, BS, Chemical Engineering

CIQA President and CEO.
I've been working in validation engineering since 1992 with many multinational
pharmaceutical companies. I love sharing my passion and knowledge with others. If you
have any questions about anything (or just have general questions). I will be more than
happy to assist you. You can count on the BEST customer service on CIQA. I go to great
lengths to make sure my clients are 100% satisfied with their purchases and check
emails/messages consistently throughout the day. You can rest assured that everything
being sold here is as-described or your money back. I look forward to working with you!

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