Microbiology in Workplace - Pharmaceutical Quality ...€¦ · Training Outcome of the Module: ... are bacteria and fungi. ... GMP Training – Microbiology in the Workplace by

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Microbiology in Workplace

GMP Training – Microbiology in the Workplace by www.gmpsop.com


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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.


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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The right physical environment means having the right

combination of:

Environment (e.g. the level of oxygen)

Temperature

pH


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.


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


Pseudomonas aeruginosa

Salmonella sp.

People, Water

People

Water, Wet Equipment

Raw Materials

Oral Liquids

E. coli


Salmonella sp.

People, Water

People

Raw Materials

Inhalants

E. coli


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


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.


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.



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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.



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TAKE THE

TEST NOW

Number of questions: 10

No time limit

Allow you save and finish at a later date

Allow you to go back and change your answer

Attempting each question is mandatory

Pass mark at and above 70%

Print results and certificates

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Documents

Microbiology in Workplace - Pharmaceutical Quality ...€¦ · Training Outcome of the Module: ... are bacteria and fungi. ... GMP Training – Microbiology in the Workplace by