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The history of clean rooms dates back to Atomic Age and greatly enhanced in the Space Age.
However, its roots go back hundreds of years to Swiss watchmakers who, to prevent dust
from falling on their sensitive timepieces when they were not being worked on, covered them
with a small bell jar. In the 1960 Willis Whitfield pioneered the clean bench, a means of
conducting clean work in a small space.cTo keep a room very clean, let air be the janitor ²
a³janitor´ sweeping the premises every six seconds.[2] This new technology was embraced
by the sterile manufacturing industry as a means of compliance of GMP. In the late 1960¶s
and early 1970¶s regulatory authorities had become more stringent. The main drive for this is
not that the regulators are making new rules but rather technology has improved industries
ability to address key issues in the regulatory world. Thus, the concept of the term ³current´ in
current Good Manufacturing Practices is a reality which can be demonstrated when new
technologies come into play, they change the nature of industry practice and thus change
what is current from a regulatory view.

The costs for poor operations, poor maintenance and poor personal practices in clean room
manufacturing can be high in both financial and regulatory terms.cPoor CGMP conditions at a
manufacturing facility can ultimately pose a life-threatening health risk to a patient.cAll
manufactures of medicinal products have to ensure that they products are fit for their
intended use, comply with the requirements of the marketing authorization and do not
place patients at risk due to inadequate safety, quality or efficacy. This is in effect a
quality objective. To achieve this one must have a correctly implemented system of
Quality Assurance incorporating CGMP(FDA 2l CFR parts 210 and 211) and thus
Quality Control.
These regulations,for the most part, describe what needs to be accomplished rather than how
to accomplish the requirement.

On how to accomplish them we must first understand what a clean room is, a cleanroom is a
controlled environment where products are manufactured. It is a room in which the
concentration of airborne particles is controlled to specified limits.. These contaminants are
generated by people, process, facilities and equipment. They must be continually removed from
the air. To employ good operations one has to build quality into the premises and control the
environment.

FDA 21 CFR 211.42(c) states, in part, that "?  


    
    
      
 
         


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The areas of manufacture must have a separate unit of operation that control to different
degrees, depending on what is being done, the air quality. The design of an area should be
based on satisfying microbiological and particle standards defined by the equipment, product
exposure, as well as the operation in the area¢ Particles are significant because they can enter
a product and contaminate it physically or by acting as a medium for microorganisms. The
control of this is achieved by HVAC systems Cleanrooms are designed to achieve and maintain
a airflow in which essentially the entire body of air within a confined area moves with uniform
velocity along parallel flow lines. This air flow is called laminar flow. The more restriction of air
flow the more turbulence. Turbulence can cause particle movement. Filtration is used such as
HEPA(High Efficiency Particulate Air Filter - These filters are extremely important for
maintaining contamination control. They filter particles as small as 0.3 microns with a 99.97%
minimum abilty to collect particles. In addition to the HEPA filters commonly used in
cleanrooms, there are a number of other filtration mechanisms used to remove particles from
gases and liquids such as cmembrane filters which allow the filtering of compressed gases to
meet an appropriate high-quality standard. These filters are essential for providing effective
contamination control.

21 CFR 211.42(b) states, in part, that "


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Both personnel and material flow should be optimized to prevent unnecessary activities that
could increase the potential for introducing contaminants to exposed product, container-
closures, or the surrounding environment.cAny intervention or stoppage during an aseptic
process can increase the risk of contamination. Thus the use of automation and good
engineering that increase process flow and reduce product handling should be incorporated.

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A well-designed aseptic process minimizes personnel intervention. As operator activities


increase in an aseptic processing operation, the risk to finished product sterility also increases.
To ensure maintenance of product sterility, operators involved in aseptic manipulations should
adhere to the basic principles of aseptic technique at all times. Personnel can significantly affect
the quality of the environment in which the sterile product is processed. Due to this personal
micro monitoring should be carried out.

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Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-
defined written program and scientifically sound methods. The monitoring program should
cover all production shifts and include air, floors, walls, and equipment surfaces, including the
critical surfaces that come in contact with the product, container, and closures.cSOPs should be
established in such areas ash as (1) frequency of sampling, (2) when the samples are taken
(i.e., during or at the conclusion of operations), (3) duration of sampling, (4) sample size (e.g.,
surface area, air volume), (5) specific sampling equipment and techniques, (6) alert and action
levels, and (7) appropriate response to deviations from alert or action levels.

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All in-process data must be included with the batch record documentation.. Review of
environmental and personnel monitoring data, as well as other data relating to acceptability of
output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper
functioning of equipment (e.g., batch alarms report; integrity of various filters), should be
viewed as essential elements of the batch release decision¢c
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The implemtation of a live and active quality system incorpating CGMP will ensure
compliance. This is further reinforced by the FDA taking a ³risk assessment´ approach to
enforcement of the regulations. This means that the agency will target those products that
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reflect the greatest threat to the safety of public health. Sterile dosage forms will be high on
the list.

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This article will show that employing good operations, good maintenance and personal
practices are essential in clean room manufacturing. The consequences of non compliance of
CGMP has the possibility of being financially large, i.e. loss of market share, loss of public
confidence, loss of the business. It is a legal requirement to implement CGMP of the
marketing authority. It is more importantly a morale issue that could pose a treet to human
life. Due to this compliance is of utmost importance.
It can be achieved based on a correctly implemented system of Quality Assurance
incorporating CGMP(FDA 2l CFR parts 210 and 211 or other marketing authority CGMP)
and thus Quality Control.
The article will follow FDA regulations followed by the means and the µknow how¶ on
achieving compliance.
It will draw on the Regulations, Quality Assurance, Warning letters from FDA and
some antidotal evidence.

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The field of contamination control is a recent technology coming to age as part of the
Atomic Age and greatly enhanced in the Space Age.[2] However, its roots go back
hundreds of years to Swiss watchmakers who, to prevent dust from falling on their
sensitive timepieces when they were not being worked on, covered them with a small bell
jar.The American Civil War) gave impetus to the next phase in cleanliness. Due to the
immense loss of life from bullet wounds, surgeons recognized the need for steps to prevent
post traumatic infection. Lister and others developed methods to achieve this end and
sterility became a watchword in operating suites.In 1945 the need to test gas mask filters
against particulate and biological materials led to the development of the aerosol particle
counter.The final step, the development of the High Efficiency Particulate Air (HEPA) filter
was developed at Sandia Labs for the Atomic Energy Commission after World War II.
Nuclear particles which would have been deadly to personnel were isolated in process
areas with HEPA filters while allowing air to circulate in them. Willis Whitfield pioneered the
clean bench, a means of conducting clean work in a small space.[1] White rooms had been
used during W.W.II to assemble contamination-sensitive parts such as gyroscopes. These
rooms used filtered air but not as highly filtered as HEPA air.

cFinally,
the Space Age with its requirements for both particulate and film cleanliness
promoted contamination control technology. Through the 60's documents such as FED
STD 209a, NASA SP-5076, "Contamination Control Handbook", NASA SP-4074, "Clean
Room Technology", NASA SP-5045, "Contamination Control Principles", and AF-TO-00-
25-203, "Contamination Control of Aerospace Facilities, US Air Force"[2] were written.
These documents stated principles which are still relevant today.

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The pharmaceutical industry embraced this new technology as a means of compliance of
regulatory authorities drive of CGMP in the same period.

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Clean rooms have to be separate to other operational procedures. The microbiological impact
have to be incorporated into the design of the space. Room finishes are hard and easily
cleanable, minimal/no crevices. Material and personal flow are unidirectional in critical area¶s.
Equipment placement and ergonomics are important in maintaining product/process integrity
and operator safety. Air Flow: unidirectional in critical operations to protect product exposed to
the room environment. HVAC, controls, zoning, and pressurization are in place to protect
product, control contamination,and keep people comfortable.
The air is classified by the following tables:

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Achieving a compliant cleanroom manufacturing operation requires the use of
increasing levels of environmental cleanliness, or ³zones.´ The figure below a typical zoning,
along with a typical air pressurization cascade from critical to noncritical zones. In noncritical
peripheral areas can be downgraded to a Controlled Not Classified (CNC), where the room is
designed to meet Grade D performance parameters but is not typically validated.

To maintain air quality in areas of higher cleanliness, it is important to achieve a proper airflow
and a positive pressure differential relative to adjacent less clean areas.The people and
material flow are controlled by airlocks with alarmed doors. The diagram below demonstrates
this in a Bio manufacturing plant
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[4]

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Pressure cascade below:

[4]
A differential of 15 Pascals between each air classifications. Controlled by airlocks.

To achieve this, the air most be filtered by HEPA filtration. Different areas of classification
require different HEPA filters and cmembrane filters which allow the filtering of compressed
gases to meet an appropriate high-quality standard. Gases used such as air, nitrogen, and
carbon dioxide are often used in cleanrooms and are frequently employed in operations
involving purging or overlaying. Sterile membrane filters should be used for autoclave air lines,
lyophilizer vacuum breaks, and tanks containing sterilized materials. Holding tanks containing
sterile product should be held under positive pressure to prevent micro biologicial growth

[3]
The above diagram is unidirectional flow cleanroom with HEPA and membrane filtration in the
ceiling. The number of air changes is determined by monitoring and justified for the area of
classification. This is done by particle monitoring and velocity monitoring. Changes in velocity
across the membrane of a filter can indicate a possibility of contamination.cLeak testing
should be performed on filters as part of continuous maintenance program.To detect integrity
breaches around the sealing gaskets, through the frames, or through various points on the
filter media. Thereafter, leak tests should be performed at suitable time intervals for HEPA
filters in the aseptic processing facility. For example, such testing should be performed twice
a year for the aseptic processing room.
Smoke studies should be conducted that demonstrate unidirectional airflow and sweeping
action over and away from the product¢cHowever, even successfully qualified systems can be
compromised by poor operational, maintenance or personnel practices
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The cost of A zoning is high to run and maintain. So the thinking would be to reduce the A
zoning area with barrier isolators. The diagram below illustrates this;

A zoning (criticial area) reduced with isolators


above and below.[3]

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Environmental monitoring programs for clean room manufacturing are composed from the
analysis of personnel, processes, raw materials,and finished products.
Evaluating the quality of air and surfaces including personal in the cleanroom environment
should start with a well-defined quality system and scientifically sound methods that are
evaluated to ensure they operate as intended The monitoring program should cover all
production shifts and include air, floors, walls, and equipment surfaces, including the critical
surfaces that come in contact with the product, container, and closures. Written procedures
(SOP¶s) should include a list of locations to be sampled. Sample timing, frequency, and location
should be carefully selected based upon their relationship to the operation performed. Samples
should be taken throughout the aseptic processing facility (e.g., aseptic corridors, gowning
rooms) using scientifically sound sampling procedures. Sampling sizes should be sufficient to
optimize detection of environmental contaminants at levels that might be expected in a given
clean area.
Risk management should be incorporated to show area¶s that pose the most microbiological
risk to the product and become a critical part of procedures. It is especially important to monitor
the microbiological quality of the aseptic processing clean area to determine whether or not
aseptic conditions are maintained during filling and closing activities. Montoring should be from
contact plates used for flate surfaces such as walls, ceilings,uniforms. Difficult surfaces can be
swabbed or rinse swabbed.Settle plates for air. Air and surface samples should be taken at the
actual working site and at locations where significant activity or product exposure occurs during
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production. Critical surfaces that come in contact with the sterile product should be sterile.
When identifying critical sites to be sampled, consideration should be given to the points of
contamination risk in a process, including factors such as difficulty of setup, length of
processing time, impact of interventions. Critical surface sampling should be performed at the of
the aseptic operation to avoid direct contact with sterile surfaces during processing.
Personal are the highest risk in a clean room from both viable and non viable particles and
hence µGowning¶. The table below shows gowning requirements for zoning area¶s.

c Hair net, shoe covers, lab coat, (optional cover of facial hair)

c Same as D but gloves and facial hair cover required


c Same as C with a coverall
c Same B but with facemask, boots, hood with three seals, neck, wrist, and ankles

Therefore training of personnel in aseptic techniques and proper gowning must be a priority.
Routine microbiological monitoring of garments and finger impressions must be completed to
determine general aseptic techniques. In general, microbiological sampling of the personnel
includes contact plate samples of; right chest, left chest, forehead ,right sleeve, left
sleeve,right hand glove covers and left hand glove covers. A program of evaluation of training
and support procedures should be implemented.
Sanitization of hands before and after every working day reduces the possibility of microbial
contamination. Gloves are either sanitized or a new pair before testing the next sample. Hair
and body must be cleaned daily. The use of cosmetics and jewelry are not allowed. Personnel
with a contagious disease such as cold, flu, and pink eye must stay away from controlled
environments.

      


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  [5]. Once the trends are determined, then limits are set upon historical,
regulatory, and industry guidelines. Alert limits are values that when exceeded point towards
a potential deviation from the system operating normally. Action limits values when exceeded
show the system is in non compliance and an investigation report and corresponding
corrective actions must be performed and implemented. Some companies operated that if 2-3
alert limits are exceeded that this constitutes action limits. If an investigation is needed to
investigate any deviations from the established values, proper documentation of the
investigation, and corrective action must be completed within reasonable time. These
investigations are usually completedwithin 1±3 months. Improper or late closure of an
investigation is one of the major reasons for noncompliance with CGMP regulations. The type
of corrective actions that are implemented when an action level has been exceeded are
typicially , sampling and testing are immediately repeated if conditions indicate that the
product quality has been compromised. Sanitization procedures are reviewed and repeated.
Retraining of personnel is performed if the investigation report indicates analyst error. Review
of controlled environment certifications might indicate system breakdown during
manufacturing, sampling, and testing. Basically, all thesystems and validation procedures are
reviewed to determine the root cause ofthe action level. If there is an indication that the
product manufactured has
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been compromised, the batches are placed on hold until the investigation is completed and
the product is cleared for release.

An antidotal reference by a colleague who worked for An American company where one
individual when de-gowning discovered a µcricket¶ on his shoe beneath his shoe cover. As it
was put µall hell broke lose¶. Which no doubt covered the procedures above.

The FDA warning letter below enforces the points above.

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21 CFR 211.56(b) states that %


 
         
        
   
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While non-product contact, such as tables, racks, carts, etc, are cleaned at intervals, product
contact equipment, such as tanks, pumps, piping, etc., must be cleaned more frequently
(typically between product batches or change-overs).
Product contact equipment also consists of fixed and portable equipment. Fixed equipment is
disassembled with some components removed from the room for cleaning out of place (COP)
in a purpose-built room. Remaining components are cleaned in place (CIP) by flushing the
system with a series of solutions and rinses while the system is closed. Control of these fluids
is managed by both the process equipment and a CIP system (typically a skid) control units..
As the equipment moves through the cleaning process, the surrounding environment
increases in cleanliness to correspond with the state of the equipment being cleaned. This
typically means that the room(s) will be designed to meet a Grade D/C environment, with local
B/A.
The non-product contact area¶s should be cleaned and disinfected. The cleaning process
should be validated and recorded. The disinfectant should be rotated.

Sterilization of equipment that is product contact is done but must be proven that the system
effectively kills all viable micro organisms.cEquipment sterilized in place (SIP) is typically
achieved through the introduction of pure steam in a closed system for a prescribed interval of
time and temperature. Equipment that can not be sterilized in this manner are placed into grade
A environment before process opertions. They are either either be chemically sterilized,
irradiated, or purchased as being sterilized.
The sterilization of the end product if possible should be µterminal sterilizated¶ but not all
products can be.Such methods as filtration, moist heat, dry heat, chemical vapours, and
radiation should be employed.

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21 CFR 211.100(a) states that %


 
       
    
 
  
 
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All in-process data must be included with the batch record documentation.. Review of
environmental and personnel monitoring data, as well as other data relating to acceptability of
output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper
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functioning of equipment (e.g., batch alarms report; integrity of various filters), should be
viewed as essential elements of the batch release decision.

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Ease of maintenance is of importance. Technicial area¶s which allow access to maitance staff
with out disruption to zoning. Clean rooms can have access to HVAC systems through walkable
ceilings also instrumentioncan be housed there. Maintenance chases or grey areas can be
employed for piping , valves etc and can be controlled unclassified. A sample can be seen
below:

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A quality system incorporating CGMP will ensure continues compliance. But the system will
ultimately fail if poor maintenance is carried out and could potentially endanger life.
Maintenance should be schduled and preventive in nature which in turn will save money in
down time. It should be recorded and well documented. Good maintenance is at the heart of
the overall system i.e. HVAC, equipment etc.
Personal practices are utmost importance as they pose the largest micro biological risk in a
clean room operation. The number of people who are in the rooms should be kept to minimum,
people intervention in the process should also be kept to minimum. Personal should be trained
and evaluation of the training effectiveness should be established. Good operations
encompasses the overall process. Manufacturing operations, according to CGMP, means that
the process has a set of controls in the design and production processes to assure
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a quality finished product.

The financial cost for non compliance is huge, loss of market, plant closure, brand integrity etc.
But more importantly is patient safety once this area is engraved into a quality policy and
allowing the air to be the janitor, the rest will follow.

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1. ,  1 2 !   3! 1  4! ³Current Good Manufacturing
Practice in Manufacturing, Processing, Packing, or Holding of Drugs,´ Part 210±211 (US
Printing Office,Washington, DC, revised April 2000).

2.www.fda.gov/history.htm

3. Clean room design. By W.White. Published by John Wiley & Sons. 1999c
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4. Good Design Practices for GMP Pharmaceutical Facilities. Edited by A.Signore and Terry
Jacobs. Volume 146.

5.Microbial Contamination Control in the Pharmaceautical Industry.Volume 142. Edited by


Luis Jinenez.

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