microbiology in workplace - pharmaceutical quality ...€¦ · training outcome of the module: ......
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Microbiology in Workplace
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Training Outcome of the Module:
Micro-organisms are a group of organisms that include bacteria, moulds, yeasts,
and viruses. They are also very adaptable and can live and multiply in conditions
other living things cannot survive in. Micro-organisms are also naturally all
around us in the environmental air, on our skin, within row materials and water,
on packaging, and on production equipment.
Microbiology is the scientific study of microscopic organisms, often called "micro-
organisms" or "microbes". Although micro-organisms are small, the mass of
microbial life on earth is 25 times greater than the total mass of animals. The
external surfaces of all animals and plants are covered with micro-organisms,
not to mention animals' internal surfaces. The human body contains about 100
trillion microorganisms.
This module introduces you to the world of micro-organisms and the potentially
bad effects they can have on the products you help to manufacture. The module
also introduces you to the methods needed to control micro-organisms.
At the end of this module, you will be able to:
Describe what types of micro-organisms may be found in pharmaceutical
products, water, and the environment
Identify the major sources of microbial contamination and what is considered
to be "objectionable"
Identify microbial contamination problems in the workplace
Identify procedures to reduce the chance of microbial contamination
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Medicine is taken when a person isn't well, has a disease or infection, or has a
problem with their immune system. These conditions make people more
vulnerable to microbial infection, and therefore, consuming products that have
contamination may make them sicker.
We do know, though, that certain products are more at-risk than others. For
example, sterile products must have zero-allowed bio burden; topical and
intranasal products may only have low bio burden; and oral liquids and dry solid
products have less restricted bio burden.
The cGMPs also require manufacturers to keep potential bio burden
contamination below very strict levels.
What do the cGMPs say?
US FDA CFR 211
§ 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent objectionable
microorganisms in drug products not required to be sterile, shall be
established and followed.
(b) Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established
and followed. Such procedures shall include validation of any sterilization
process.
International GMPs
5. Production – General
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5.10. At every stage of processing, products and materials should be protected
from microbial and other contamination.
Annex 1 Sterile products – General
3. Clean areas for the manufacture of sterile products are classified according to
the required characteristics of the environment. Each manufacturing operation
requires an appropriate environmental cleanliness level in the operational state
in order to minimize the risks of particulate or microbial contamination of the
product or materials being handled.
Overview:
In the pharmaceutical industry, the major types of micro-organisms of concern
are bacteria and fungi. Manufacturers of biological products are also concerned
with the presence of viruses in their products.
Some species of bacteria are very hardy. They can live in extremely harsh
environments, such as in high salt concentration, acids, or high temperatures.
Manufacturers need to control these micro-organisms to ensure that they stay
at acceptable levels. Micro-organisms higher than acceptable levels may harm
the products or consumers.
GOOD TO KNOW – VIRUSES
Viruses are much smaller than bacteria and readily pass through bacteria-
retaining filters.
In manufacturing environments where living cells are involved in the
manufacturing process, viruses are of concern. For this reason, manufacturers
of biological products generally include a virus reduction step in their
processes. This may be by chemical means or application of heat.
Because of the difficulty in removing viruses, they need to be excluded from
"at risk" products. Typically, materials are screened for undesirable viruses.
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GOOD TO KNOW – SPORES
Bacteria are usually vegetative cells that can grow and reproduce easily.
However, some bacteria and fungi can form chemical and heat-resistant spores
when the conditions surrounding them are harsh. They are most commonly
found in soil organisms, like Bacilli and Clostridia.
Spores do not grow or reproduce. Instead, they lie dormant until environmental
conditions are conducive to growth. When this occurs, a spore will germinate
and form a vegetative (growing) cell.
Spores can survive extreme heat, drying, or exposure to toxic chemicals, such
as disinfectants. For example, the spores of Clostridium Botulinum can survive
boiling for several hours. Most spores can withstand temperatures of 80°C for
several minutes, whereas most vegetative (growing) cells are killed by
temperature of about 60°C
Because spores are so difficult to kill, they need to be excluded from product.
This is normally achieved by protecting the manufacturing environment from
outside dirt and air. As germination may be triggered by brief exposure to heat,
water, or by mechanical forces, manufacturing facilities should also be kept
dry.
Roles of bacteria and fungi
Micro-organisms are essential for your health. The normal flora that covers your
skin and internal surfaces prevent disease-causing micro-organisms from taking
over.
Bacteria and fungi play a vital in the decomposition of all organic matter,
returning carbon, nitrogen, and other essential elements back to the soil.
Bacteria and fungi also play important roles in industry, for instance, in the
production of food, vaccines, and antibiotics. Probiotic bacteria, which can be
found in yoghurt, helps the body remove cholesterol. Yeasts, a type of fungus,
are used in the production of bread and alcohol. Moulds, another fungus, make
penicillin.
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Of the several thousand bacterial and fungal species known, only relatively few
commonly cause disease. Others are "opportunistic" and infect people when they
are immunocompromised (sick or run-down). Infections such as sore throats,
tetanus, cholera, and tuberculosis are caused by bacteria. Some fungal species
are responsible for the deterioration of textiles and wood, while others cause
diseases like athlete's foot and thrush.
RHYZOPUS SP. ASPERGILLIUS SP. PENICILLIUM SP.
GOOD TO KNOW - DIFFERENCE BETWEEN BACTERIA AND FUNGI
Although they can both be microscopic, one key difference between bacteria
and fungi is that bacteria are "prokaryotes" (one-celled organisms, no nucleus)
while fungi are "eukaryotes" (generally multi-celled organisms that contain
nuclei).
Regardless of how many cells micro-organisms contain, each may pose distinct
risks to pharmaceutical product.
Basic classification of bacteria
There are different ways of classifying bacteria, based on different characteristics
they may or may not exhibit.
Size
Structure and shape
Oxygen requirements
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Cell structure (bacteria only)
Size
Bacteria are microscopic, and range in size from 0.5 microns to 10 microns,
measured across. Fungi can be microscopic as well (e.g. moulds and yeasts), but
can also be macroscopic (e.g. mushrooms).
Note: 1000 microns is equal to 1 millimeter. The thickness of human hair can be
between 40-300 microns.
SIZE
Streptococci
075-1.25 microns
Shigella (causes
dysentery) 2-3 microns
E. coli
1.1-1.5 microns x 2-6
microns
Structure and shape
Bacteria come in many shapes, but the most common are rods (bacilli), spheres
(cocci), and spirals (spirilla).
STRUCTURE AND SHAPE
Bacilli
E. coli, Clostridium
botulinum
Cocci
Staphylococcus (e.g. S. aureus).
Spirilla
Spirochete (causes syphilis)
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Oxygen requirements
Bacteria and fungi are also classified by their requirements for oxygen. They can
be aerobes (needing oxygen), anaerobes (cannot grow in the presence of oxygen),
and facultative anaerobes (can grow with or without the presence of oxygen).
OXYGEN REQUIREMENTS
Aerobic
Staphylococcus aureus
Anaerobic
Clostridium botulinum
Facultative anaerobic
E. coli
Cell structure (bacteria only)
Another way to classify bacteria is based on their cellular structure, depending
on how they react to gram stain. Some cell walls will retain the gram stain ("gram-
positive") and turn blue as a result. Other cell walls won't retain the stain ("gram-
negative"), and become red.
CELL STRUCTURE (BACTERIA ONLY)
Gram-positive
Clostridium botulinum
Gram-negative
E. coli
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Micro-organisms can rapidly multiply in the presence of stagnant water. This is
why equipment must be stored dry.
In addition, topical creams have strict limits on bio burden, since creams are
often used by patients on damaged or broken skin. If the product is
contaminated, patients may become infected.
What do the cGMPs say?
US FDA CFR 211
§ 211.67 Equipment cleaning and maintenance.
(a) Equipment and utensils shall be cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or contamination that would
alter the safety, identity, strength, quality, or purity of the drug product
beyond the official or other established requirements.
(b) Written procedures shall be established and followed for cleaning and
maintenance of equipment, including utensils, used in the manufacture,
processing, packing, or holding of a drug product
International GMPs
Equipment
3.34 Manufacturing equipment should be designed, located and maintained to
suit its intended purpose.
3.36 Manufacturing equipment should be designed so that it can be easily and
thoroughly cleaned. It should be cleaned according to detailed and written
procedures and stored only in a clean and dry condition.
3.37 Washing and cleaning equipment should be chosen and used in order not
to be a source of contamination.
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Overview
To properly control micro-organisms, we need to understand what makes them
grow and multiply.
Micro-organisms only need small amounts of nutrients and moisture to grow,
which is why manufacturing facilities need to be kept clean and dry.
The growth of micro-organisms depends on the combination of the below factors:
Nutrients
Moisture
Physical environment
GROWTH OF MICRO-ORGANISMS
Nutrients
The main nutrients are:
Carbon, from carbon dioxide (CO2) or organic
compounds
Nitrogen, from organic compounds such as amino
acids, and inorganic compounds such as ammonia
Hydrogen, oxygen, sulphur, and phosphorus, which
are all found in water and the atmosphere.
Moisture
Just like humans, micro-organisms need water to grow.
Water is responsible for a large majority of a cell's
makeup, and has roles in nutrition and cellular
metabolism.
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Physical environment
The right physical environment means having the right
combination of:
Environment (e.g. the level of oxygen)
Temperature
pH
Physical environment
Micro-organisms require varying amounts of gases, specifically, oxygen (O2),
carbon dioxide (CO2), and nitrogen (N2). As you learned in the previous topic,
micro-organisms needing O2 are called aerobes; those that can't tolerate it are
anaerobes; those that can grow with or without O2 are the facultative anaerobes.
CLASSIFYING MICRO-ORGANISMS BY OPTIMUM TEMPERATURE
Psychrophiles Low (7°C - 15°C)
Mesophiles Moderate (25°C -40°C)
Thermophiles High (>45°C)
GROWTH OF MICRO-ORGANISMS
Temperature:
Temperature affects the growth
rate of micro-organisms.
Generally, lower temperatures
inhibit growth, while warmer
temperatures promote growth.
Although optimum temperatures
will vary from species to species,
the pattern of growth will be the
same.
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pH:
The pH range in which bacteria
can grow is usually between 4
and 9, with an optimum range
usually between 6 and 8. Moulds
and yeasts have a broader pH
range than bacteria, and their
optimum is lower, usually 5-6.
Different species have adapted to
grow at different pH values,
which is the reason that some
bacteria are able to grow in
disinfectants and other strong
chemicals
How bacteria grow
Bacteria multiply by a process known as binary fission.
This means that each bacterial cell divides into two living cells so that the
population doubles in number with each division.
The population of bacteria is said to grow exponentially, and will continue to
expand until the nutrients run out or environmental conditions change.
To multiply, bacteria usually require:
Moist conditions
Adequate temperature
Adequate nutrients
No inhibiting agents
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GOOD TO KNOW - DIFFICULTY IN COUNTING MICRO-ORGANISMS
As micro-organisms are constantly multiplying and dying, to get a true count,
multiplication must be slowed or stopped altogether.
Since micro-organisms rarely occur alone, estimates must be made. Estimates
can be made through a process called Total Viable Aerobic Count (TVAC),
which counts the number of colony forming units (CFUs). CFU counting
assumes one colony has originated on the media from one cell, and as such,
would introduce significant error into the count.
Some micro-organisms do not grow together due to toxicity, or because of
different temperature, moisture, oxygen, and nutrient requirements.
How fast can bacteria multiply?
The typical generation time is 30-60 minutes. The time interval ("generation time"
or "doubling time") required for bacteria to divide, and therefore double in
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number, varies for each species. It may be as short as 15 minutes for E. coli, or
as long as 15 hours for M. tuberculosis.
This means that, if growth were unlimited, in 24 hours a single E. coli bacterium
could multiply enough to fill a total volume the size of an average factory! This
doesn't happen, of course, because other factors come into play that help
stabilise or reduce microbial populations, e.g. changes in oxygen, temperature,
pH, and the amount of nutrients.
How bacteria die
A population of micro-organisms, when faced with adverse conditions such as
disinfectants or increasing heat, will not die instantly. Some of the micro-
organisms will die immediately, while others will take several minutes. Some may
even survive. The pattern of death is also exponential.
Therefore, enough time must be allowed for the cleaning or sanitizing agent to
take effect in order to effectively reduce the number of micro-organisms in the
workplace.
Micro-organisms are mostly killed by exposure to heat above 55 - 60°C for
periods of time. The heat breaks down the cell wall, which kills the micro-
organism. The cell walls of spores, however, are resistant to anything but high
heat.
Similarly, alcohol is a good general sanitizing agent, but there are some micro-
organisms that are not killed by alcohol (such as spores).
A combination of heat and alcohol provides two methods of sanitizing. Of course,
sanitation will only be effective if a validated procedure is followed. Pay particular
attention to:
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pre-cleaning to remove most of the chemical residues and bio burden
the length of time the heat and sanitizing agents are applied for: too short an
exposure time will be less effective.
What do the cGMPs say?
US FDA CFR 211
§ 211.67 Equipment cleaning and maintenance.
(a) Equipment and utensils shall be cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or contamination that would alter
the safety, identity, strength, quality, or purity of the drug product beyond the
official or other established requirements.
§ 211.84 Testing and approval or rejection of components, drug product
containers, and closures
6) Each lot of a component, drug product container, or closure that is liable to
microbiological contamination that is objectionable in view of its intended use
shall be subjected to microbiological tests before use.
International GMPs
3.36 Manufacturing equipment should be designed so that it can be easily and
thoroughly cleaned. It should be cleaned according to detailed and written
procedures and stored only in a clean and dry condition.
5.10 At every stage of processing, products and materials should be protected
from microbial and other contamination.
5.19 Cross-contamination should be avoided by appropriate technical or
organizational measures, for example:
…
e) using cleaning and decontamination procedures of known effectiveness, as
ineffective cleaning of equipment is a common source of cross-contamination;
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Overview
Objectionable organisms
Some micro-organisms are of particular concern in certain dose forms.
Objectionable organisms are organisms that shouldn't be present in a product,
because of:
Product degradant on, making products ineffective
Consumer safety, as products could become health risks
GOOD TO KNOW - REGULATORY VIEW ON MICROBIAL LIMITS
The significance of micro-organisms in non-sterile pharmaceutical products
should be evaluated by the manufacturer in terms of the following:
Use of the product (topical or oral)
Nature of the product (supports/inhibits growth)
Potential hazard to the user (children/sick/old)
It is therefore very difficult to set hard and fast regulatory limits for micro-
organisms, except for specific products.
GOOD TO KNOW - MICROBIOLOGY "FACTS" END QC LABORATORY CONTROL
It would be virtually impossible to completely validate test procedures for
every organism that may be objectionable. However, it is a good practice to
assure that inhibitory substances in samples are neutralized.
For products such as topicals, inhalants, or nasal solutions where there is
a major concern for microbiological contamination, isolates from plate
counts, as well as enrichment testing, should be identified.
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It is recognized that pseudomonads are objectionable if found in a topical
product or nasal solution in any numbers. There are no test methods
provided in the USP that will enable the identification of the presence of this
micro-organism.
Your Product "Objectionable" Organisms Likely Sources
Cream/Ointments
E. coli
Staphylococcus aureus
Pseudomonas aeruginosa
Salmonella sp.
People, Water
People
Water, Wet Equipment
Raw Materials
Oral Liquids
E. coli
Staphylococcus aureus
Salmonella sp.
People, Water
People
Raw Materials
Inhalants
E. coli
Staphylococcus aureus
Pseudomonas aeruginosa
Salmonella sp.
People, Water
People
Water, Wet Equipment
Raw Materials
Sterile Products
All micro-organisms
People
Air
Water
Raw Materials
Dirty and We" Equipment
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Tablets/Capsules
E. coli
Staphylococcus aureus
Salmonella sp.
People, Water
People
Raw Materials
Minimizing microbes
We cannot eliminate micro-organisms. But we can minimize their numbers, or
exclude them from our manufacturing following lists a number of methods we
use to minimize micro-organisms:
Control the manufacturing environment
Wear protective clothing
Implement cleaning and sanitation programs
Keep equipment clean and dry
Maintain room pressures by keeping doors closed
Maintain a high standard of personal hygiene
Critical microbial control issues
The challenge to the industry is to minimize or, as with sterile products, totally
exclude or destroy micro-organisms from the products being manufactured.
Critical microbial control issues arise during different stages of the
manufacturing process.
These issues can arise in:
Starting materials control
Production equipment control
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Water and other critical services control
Environmental control
Personnel control
We will look at each of these issues in turn.
GOOD TO KNOW - MICROBIOLOGY "FACTS" AND MANUFACTURING CONTROL
Microbiological testing is far from absolute.
Negative test results may merely indicate insensitivity of the test.
Microbiological contamination is not evenly dispersed throughout a lot or
sample of product.
Finding a contaminant in one sample and not in another does not discount
the findings of the initial sample results.
Other organisms may mask the presence of certain organisms when
identification procedures are performed.
Control of starting materials
Starting materials must always be handled and stored in a manner to prevent
contamination. Some important handling and storage rules include:
Store starting materials clean, dry, and if necessary, cold.
Store starting materials off the ground, and under cover.
Always keep containers sealed when not in use.
Be alert to damaged packages.
Never use dirty or wet sampling or measuring equipment.
Starting materials themselves may contain potentially contaminating micro-
organisms. QC testing takes into consideration the origin of the mater al,
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intended usage, and probability of microbial contamination. Suppliers of starting
materials should also be audited, either by extended QC testing or by site
inspections.
GOOD TO KNOW - TYPICAL MICROBIAL LIMITS FOR STARTING MATERIALS
Starting material Microbial limits**
Synthetic, purified, and processed material 100 cfu/g
Processed material of natural origin 1000 cfu/g
Materials of earth origin (mined)
absence of Clostridia species 10,000 cfu/g
Natural products 100,000 cfu/g
** Absence of objectionable organisms depending on intended use.
Control of equipment
Equipment con also be a source of contamination, so there should be controls
in place that ensure equipment is kept dry and sanitary.
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GOOD TO KNOW - MICROBIAL MONITORING
Focus microbial monitoring on "at-risk" equipment, such as on topicals and
liquids lines, as well as product contact surfaces.
Monitor after cleaning or before re-use.
Periodically identify the bioload to check for objectionable organisms, and build
up a profile of them.
Control of pharmaceutical water
Water is a key ingredient of many pharmaceutical products, however, it is an
essential ingredient in promoting microbial growth.
Therefore, its microbial "'cleanliness'" is critical within pharmaceutical
companies.
Pharmaceutical water is used in two main ways: as part of product formulation,
and as a cleaning agent for equipment.
Purified water
This water is intended for the formulation of non-sterile products and final
rinsing of equipment after cleaning. Purified water is used extensively in the
plant. It is monitored by Quality Control and has specified limits for bio burden.
These limits are not failure limits but rather indicate when action should be
taken to correct the system.
Action limit 100 cfu/mL
Warning limit 10 cfu/mL
Target limit 1 cfu/mL
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Water for injection (WFI)
This water is intended for the formulation of parenteral, dialysis, or inhalant
products. It should be prepared by distillation or reverse osmosis.
WFI is usually held under high temperature (> 80°C) to ensure that there is no
chance of microbial growth. WFI is monitored by QC, usually daily, to ensure
that the system remains bio burden- and endotoxin-free.
Typical limits for WFI are:
Target: no organisms / 100 mL
Action: < 10 organisms / 100 mL and <0.25 endotoxin units/mL *
** The presence of any endotoxin in WFI is usually a major concern.
GOOD TO KNOW - ISSUES AND PROBLEMS WITH WATER SYSTEMS
These concerns are based on the product types being manufactured:
For topicals and inhalants, there must be no presence of pseudomonads in
the water testing profile.
Systems must be able to be regularly sanitized. Each unit within a water
system may have different sanitation conditions.
Manufacturers need active change control and maintenance programs.
The QC test program should carefully document:
- Sample points and timing "worst-case"
- Sufficient frequency of testing in order to generate meaningful results
Pay attention to the limits and responses to out-of-limits.
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cGMPs require manufacturers to minimize the numbers of micro-organisms from
entering production areas and products. Typical ways this can be done include
using air pressure differentials so that micro-organisms are precluded and
ensuring that operators are appropriately gowned (e.g., hat, boots, cover-alls).
Micro-organisms, particularly moulds and spores, are transmitted to rooms by
air currents. Positive filtered air pressure in rooms prevents these contaminants
from entering the rooms due to the air barrier.
What do the cGMPs say?
US FDA CFR 211
§ 211.46 Ventilation, air filtration, air heating and cooling.
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air pressure, micro-organisms, dust,
humidity, and temperature shall be provided when appropriate for the
manufacture, processing, packing, or holding of a drug product.
(c) Air filtration systems, including pre-filters and particulate matter air filters,
shall be used when appropriate on air supplies to production areas....
§ 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent objectionable
microorganisms in drug products not required to be sterile, shall be established
and followed.
b) Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established and
followed. Such procedures shall include validation of any sterilization process.
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International GMPs
PREMISES
General
3.1. Premises should be situated in an environment which, when considered
together with measures to protect the manufacture, presents minimal risk of
causing contamination of materials or products.
Annex 1 - Sterile Products
29. A filtered air supply should maintain a positive pressure and an air flow
relative to surrounding areas of a lower grade under all operational conditions
and should flush the area effectively. Adjacent rooms of different grades should
have a pressure differential of 10-15 pascals (guidance values).
Control of the environment
When products are exposed to the environment, the environment must be
controlled. Some ways of achieving environmental control include the
implementation of:
Air handling systems
Designated manufacturing zones
Cleaning programs
Air handling systems
Air handling systems include ways to filter the air, for example, with the use of
HEHA (high-efficiency particulate air) filters that trap micro-organisms in the air.
The air handling systems should generally maintain positive air pressure relative
to the outside environment in order to prevent particles and micro-organisms
from entering the facility, and particularly the manufacturing areas.
This is one of the main reasons that all doors should be kept closed.
Designated manufacturing zones
There should be designated manufacturing areas at the facility to keep products
away from the outside, "non-controlled", environment.
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Within the designated zone, doors and windows should be kept shut, and people
and personnel entering the designated zone should change their outer garments.
Cleaning programs
Cleaning programs at the facility should include keeping manufacturing areas
clean and dry at all times, as well as regular checks and periodic cleaning of the
air ducts and filters.
In particular, surfaces that may catch dust should be regularly cleaned, such as
ledges, door handles, piping, etc.
Personal hygiene practices
People are potentially the largest source of micro-organisms, and are the hardest
factor to control.
In the pharmaceutical industry, companies should ensure that:
Staff wear protective garments (including caps and shoes) that are clean, and
are only worn in designated processing areas.
Product isn't handled with bare hands.
GMP induction and ongoing GMP training include personal hygiene and
sanitation rules.
Personnel wash hands after visiting the toilet.
Micro-organisms make up more than 50% of the weight of human faeces
(approximately 1 trillion/g). Even after washing hands, your skin will again
contain over 20,000 microbes per cm2.
Airlocks between toilets and production areas
Any staff infections are reported to supervisors
There are policies in place prohibiting food, cosmetics and jewelry in
production areas.
GMP Training – Microbiology in the Workplace by www.gmpsop.com
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Page 26 of 27
Summary
This module provided an introduction to the control and management of
manufacturing of pharmaceutical products.
Key points covered in this module:
Micro-organisms are very adaptable, and are found everywhere.
Micro-organisms need only small amounts of nutrients and moisture to grow,
and they can grow very quickly.
Objectionable organisms should not be present in a product because they can
reduce the product's effectiveness and cause possible harm to consumers.
Although micro-organisms cannot be necessarily eliminated entirely,
manufacturers need to keep micro-organisms at acceptable levels.
To reduce the numbers of micro-organisms in the workplace, there must be
strict controls in place over the manufacturing environment, starting
materials, equipment, pharmaceutical water, the environment, and personal
hygiene.
GMP Training – Microbiology in the Workplace by www.gmpsop.com
Copyright©www.gmpsop.com. All rights reserved Unauthorized copying, publishing, transmission and distribution of any part of the content by electronic means are strictly prohibited.
Page 27 of 27
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Number of questions: 10
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Allow you save and finish at a later date
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Attempting each question is mandatory
Pass mark at and above 70%
Print results and certificates