GMP requirement to control microbial contamination in non sterile product (Includes personnel, production, facility, utility, equipment) Glossary At restA term for the static state with all services operating, but without personnel present. Bioburden The total microbial load with which an object or sample is contaminated. Biofilm An organized microbial system consisting of layers of microbial cells associated with surfaces, often with complex structural and functional characteristics. Biofilms have physical/chemical gradients that influence microbial metabolic processes. They can form on inanimate devices and also cause fouling . CFU (Colony Forming Unit)Viable micro-organisms (bacteria, yeasts and mould) cap able of growth under the prescribed conditions (medium, atmosphere, time and temperature) develop into visible colonies (colony forming units) which are counted. The term colony forming unit (CFU) is used because a colony may result from a single micro-organism or from a clump/cluster of micro-organisms. It is normally expressed as CFU per g or mL. CleaningThe removal of soil from a surface. Clean roomA room in which the concentration of airborne particles is controlled to a defined standard. This is achieved by controlling the introduction, formation and retention of particles. Contact timeThe total time an organism is exposed to the antimicrobial action of a disinfectant. ContaminantA foreign agent not introduced as part of processing, such as airborne particulates or adventitious micro-organisms. Dead legAny length of pipework that does not allow effective circulation of its contents, resulting in the potential for contamination. DisinfectantAn agent that reduces the level of micro -organisms to one that is safe for the relevant purpose. Usually a chemical agent but sometimes may be a physical one such as X-rays or ultraviolet light. Dynamic state Refers to environmental or particle monitoring when a room is occupied by personnel. FMEA (Failure Mode and Effects Analysis) A risk assessment and risk mitigation tool. HACCP (Hazard Analysis and Critical Control Points) A formalized process by which a manufacturer ensures that all steps critical to product safety are assessed and that adequate safety procedures are identified, implemented and reviewed. HEPA (High Efficiency Particulate Air)
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GMP Requirement to Control Microbial Contamination in Non Sterile Products
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8/10/2019 GMP Requirement to Control Microbial Contamination in Non Sterile Products
A term for the static state with all services operating, but without personnel present.
Bioburden
The total microbial load with which an object or sample is contaminated.
Biofilm
An organized microbial system consisting of layers of microbial cells associated with surfaces,
often with complex structural and functional characteristics. Biofilms have physical/chemical
gradients that influence microbial metabolic processes. They can form on inanimate devices and
also cause fouling .
CFU (Colony Forming Unit)
Viable micro-organisms (bacteria, yeasts and mould) capable of growth under the prescribed
conditions (medium, atmosphere, time and temperature) develop into visible colonies (colony
forming units) which are counted. The term colony forming unit (CFU) is used because a colony
may result from a single micro-organism or from a clump/cluster of micro-organisms. It is
normally expressed as CFU per g or mL.
Cleaning
The removal of soil from a surface.
Clean room
A room in which the concentration of airborne particles is controlled to a defined standard. This
is achieved by controlling the introduction, formation and retention of particles.
Contact time
The total time an organism is exposed to the antimicrobial action of a disinfectant.
Contaminant
A foreign agent not introduced as part of processing, such as airborne particulates or
adventitious micro-organisms.
Dead leg
Any length of pipework that does not allow effective circulation of its contents, resulting in the
potential for contamination.
Disinfectant
An agent that reduces the level of micro-organisms to one that is safe for the relevant purpose.Usually a chemical agent but sometimes may be a physical one such as X-rays or ultraviolet light.
Dynamic state
Refers to environmental or particle monitoring when a room is occupied by personnel.
FMEA (Failure Mode and Effects Analysis)
A risk assessment and risk mitigation tool.
HACCP (Hazard Analysis and Critical Control Points)
A formalized process by which a manufacturer ensures that all steps critical to product safety are
assessed and that adequate safety procedures are identified, implemented and reviewed.
HEPA (High Efficiency Particulate Air)
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Describes the system for filtering (diluting) air into clean-rooms. Standard HEPA filters remove
99.97% of 0.3μm particles.
Medium (plural, media)
Any liquid or solid material prepared for the growth, maintenance, or storage of micro-
organisms.
Microbiological Control The sum total of activities undertaken to manage and mitigate risks from microbiological sources.
Microbiological Monitoring
Sampling, testing, trending and reporting activities undertaken to assess and understand the
state of microbiological control.
Objectionable organism
An organism that is risk assessed to be objectionable with respect to its potential impact to
patients. Some objectionable organisms are specified in the pharmacopoeias but these are not
exclusive and other organisms may be objectionable depending on the nature of the product,
route of administration and intended patient population.
Out-of-Specification (OOS)
An OOS result is one which fal ls outside the specifications or acceptance criteria established innew drug applications, official compendia, or by the manufacturer within their internal
procedures, e.g. Action levels for environmental monitoring data.
Out-of-Trend (OOT)
With respect to environmental monitoring data, the exceeding of an alert level or a defined
statistical signal.
RODAC (Replicate Organism Detection And Counting)
The international acronym for a contact plate (that is an agar plate, with a raised surface, applied to a
surface for the enumeration of micro-organsims).
Risk assessment
A systematic process of organizing information to support a risk decision to be made within a risk
management process. It consists of the identification of hazard and the analysis and evaluationof risks associated with the exposure to those hazards (ICH Q9).
Settle plate
An agar plate used for passive air-sampling. The plate is exposed for a fixed duration, after which
it is incubated, and the number of micro-organisms which have settled on it and have produced
colonies are counted.
Sporicide
An agent that destroys microbial spores, especially a chemical substance that kills bacterial
spores.
Water activity (aw)
A measurement of the energy status of the water in a system. It is defined as the vapor pressure of
water above a sample divided by that of pure water at the same temperature; therefore, pure distilled
water has a water activity of exactly one.
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• Where used they should be
subject to appropriate
controls to minimize the ris
contamination from this
source. E.g., they should
1. Not be left on the outle
2. Dried after use,
3.
Hung vertically in appr
locations to ensure fre
drainage,
4. Monitored and regula
cleaned,
5. Sanitized and replaced
6. Samples for microbia
monitoring should b
including the used h
Various design features may be utilized to prevent the development of
biofilms and control contamination:
1- Continual circulation with adequate flow rate (typically 1 –3 m/s) to aid the prevention of
biofilm formation and minimize dead legs.
2- The capacity to heat the water to elevated temperatures (typically 65 –85°C) forsanitization purposes
3-
Inclusion of high intensity UV lamps. The inclusion of UV lamps downstream of potential
microbial reservoirs, e.g. carbon beds, softeners, has the added advantage of enabling
ozone to be used for sanitization
• Where UV lamps are used they should be regularly checked and maintained to ensure
they are clean and provide the correct wavelength and energy output
The inclusion of filters within the distribution loop is difficult to justify and is not advisable.
Older systems, without such design features may require regular disinfection using
an oxidizing agent to control biofilm e.g. ozone, hydrogen peroxide, hypochlorite • Each of these methods has disadvantages, e.g. additional design considerations (UV light
to destroy ozone) or Health and Safety risks, and none is fully effective. Extensive flushing
is required to remove chemical residues if hypochlorite is used, which is expensive and
disruptive.
• Typically, stainless steel pipe work will be used, though systems with plastic piping have
also been used.
• Sanitary design for valves is an expectation.
• Operating procedures should require outlets to be flushed before usage To:
Ensure use of the circulating water
Remove possible stagnant water or contamination from the surface of the outlet.
• The flushing of outlets prior to sampling for monitoring purposes should be
equivalent to that applied in operational use
• The use of hoses and temporary piping is a major source of contamination
to product in non-sterile facilities and therefore their use should be
minimized.
2.3.3. Steam
• Clean steam is used for
1. Cleaning and sanitization of production tools and equipment,
2. Supply for autoclaves and
3.
Humidification of air where required.
• The microbial risk from the steam itself is low due to the physical
characteristics of steam and its production from purified water using a heat
exchange.
• Care should be taken with respect to condensation generated upon cooling
of the steam on surfaces, which may be sources of contamination that may
then be spread by the condensate.
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4- Cleaning and
Disinfection:4.1. Cleaning Documentation system
• Areas must be regularly cleaned and, where
necessary, disinfected to a written procedure
and programmed.
• Standard Operating Procedures (SOPs) are
required and need to be part of the document
control system.
• SOPs need to state the
Areas to be cleaned and their
frequency,
Materials, equipment and methods.
• A cleaning log is required which records the areas cleaned, agents used, type of
cleaning (as appropriate) and the identity initials of the operator.
4.2. Frequency
• The frequency of different cleaning and disinfectant activities will vary depending on
the risk assessment (which takes account of room usage and formulation).
For example, floors, fittings and benches may have a routine daily clean, while higher
level walls and ceilings may be cleaned less frequently, e.g. weekly or monthly.
4.3. Sequence and Method
• The method and sequences of cleaning is important; contact time, application
temperature, mechanical action and the chemistry of the cleaning agents should all be
considered during the design of the cleaning process.• Where used, all residual cleaning and sanitizing agents must be removed from
product contact surfaces to avoid product contamination
• Fittings and fixtures including door handles, light switches and telephone receivers
should be included in the cleaning regime
• Water should never be left to stand in the buckets but used and immediately
discarded to ensure that a potentially significant source of microbiological
contamination is removed as soon as possible.
• All items, including machines used for mechanical cleaning, need to be stored clean
and dry.
•
There should be a defined drying method/area and storage area, room or cupboardfor dried cleaning utensils and materials because residues of liquid and moisture
encourage microbial growth and the development of resistant strains.
• It is important that all cleaning regimes (automated and manual) are fully validated
or subject to verification to ensure that the equipment used for pharmaceutical
production is free from residues of product or cleaning material and microbial
contamination.
Sufficient time and resource should be allocated for cleaning activiti
o Hot water or hot water w
detergent followed by a h
water rinse may be all tha
necessary in some areas.
o
Whereas other facilities w
require detergent clean
followed by a disinfectan
This should be determine
and documented by the r
8/10/2019 GMP Requirement to Control Microbial Contamination in Non Sterile Products