GMP Requirement to Control Microbial Contamination in Non Sterile Products

8/10/2019 GMP Requirement to Control Microbial Contamination in Non Sterile Products

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GMP requirement to control

microbial contamination in non

sterile product(Includes personnel, production, facility, utility,

equipment)

Glossary

At rest

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)



GMP requirement to control Microbial contamination in non sterile products 2014

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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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There are a number of potential sources of

microbial contamination within a pharmaceutical

facility, including:

1.

Personnel 2.

Air/compressed

gases

3.

Process

design

4. Facility

design andlayout

5.

Equipment 6.

Water 7.

Product formulation

8. (active, starting

materials, packaging

components)

There are a number of potential

sources of microbial contamination within a pharmaceutical facility,

including:

- Personnel

• All individuals who enter the production areas at any time.

• Access to production areas must be controlled to ensure

entry is restricted to trained personnel and accompanied

visitors.

1.1.

GMP Training:

Training of below mentioned topics

• Introduction to micro-organisms and microbiological contamination control

•

Entry and exit of production facilities (including gowning)

• Personal hygiene training

• Good working practices

1.2.

Hygiene

For non-sterile manufacture the hygiene program will include:

• Medical examination upon recruitment

• A procedure for the notification of health conditions that may affect product

quality and subsequent actions to prevent contact with starting materials,

primary packaging materials and manufactured products by those personnel

with:

1-

Infectious disease

2-

Open lesions on any exposed part of body

3-

Shedding skin conditions, such as eczema or psoriasis

4-

Objectionable micro-organisms that may impact pharmaceutical

products and patients)

5-

Gastric upsets

6- Steps to be taken to prevent direct contact between the operator’s

skin and any pharmaceutical product/product contact equipment.




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• The prohibition of eating, drinking, chewing or smoking, or the storage of food, drinks,

smoking materials or personal medication in the production or storage areas

• A requirement for personnel to wash their hands before entering the manufacturing

facility

1.3. Gowning

•

In general, a non-sterile manufacturing environment will require

• Wearing of suitable protective over-garments appropriate to the

operations to be carried out generally one piece over-garments are often

used as they provide a better level of protection to both the operation and

the product

• Wearing a hair cover (e.g. mob cap), beard or moustache cover (where

applicable) and overshoes.

• Dedicated shoes are recommended for personnel working in product ion

areas for long periods

•

Requiring the removal of jewelers, in particular rings with stones andearrings, and make up

• Gloves must be worn when performing production activities (including the

handling of components) to ensure there is no contact between operators’

hands and exposed products or any part of equipment that comes

into contact with product.

• Visitors not entering production rooms may only require a laboratory coat,

rather than a one piece over-garment.

• Personnel and material flows should be considered when planning the

facility and processes. Additional care should be taken with staff movement

and production scheduling.

- Facility and Utility

Facility and equipment design cannot eliminate

microbial contamination.

But good hygienic design can mitigate several of

these risks.

For example , well designed water and HVACsystems minimize microbial ingress and aid

monitoring; equipment designs with smooth

surfaces of appropriate materials can facilitate

effective cleaning.

2.1. Material Flow

• Personnel access must only be made via changing rooms

• Access to the facility must be restricted to personnel that are fully trained and

assessed as competent to work in that area.




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• All visitors should be accompanied at all times by fully trained

personnel.

• The changing room design contributes to the assurance of

appropriate personnel access and microbial contamination control.

• The requirements for area entry must be written into procedures:

o

It is usual to have pictures of correctly clothed personnel

o

Mirrors to enable staff to check them before entry.

o

The changing room should be provided with filtered air.

o

It is useful to have a ’step over’ line or bench to define the

boundaries of clothing requirements.

o Hand washing facilities should be included in the design of

changing rooms and used prior to access to the production areas.

• A copy of the gowning procedure should be present in the changing room.

2.2 Building requirement

2.2.1. Surface

• Surfaces should be:

Smooth that will not harbor micro-organisms and can withstand the routine

cleaning regimes required .

• Floors should be:

Constructed of durable cleanable materials with minimal joins and will typically be

epoxy resin or sheet vinyl , not vinyl tiles.

• Lights should be

Encased, flush with the ceiling or wall panels and appropriately

sealed with silicone to prevent collection of dust and microbial

matter

• Coving or moulding should be:

Used at the junctions between floor and wall and between ceiling

and wall to eliminate right-angle joints and aid cleaning. The joints should be

sealed with silicone and the coving maintained in a good condition to prevent

collection of dust and microbial matter

• Sinks within the production areas should be:

Made of stainless steel and designed to be self-draining to minimize any

pooling or trapping of water and to maximize cleanability

• Benches and trolleys should be:

Made of cleanable, impermeable materials and have smooth surfaces.

The use of mobile benches can facilitate cleaning. However,where mobile units

are used, consideration must be given to maintaining cleanliness of the wheels,

e.g., through the use of sticky mats between rooms.

At points of entry to the facility or to rooms, “sticky” mats or polymeric flooring

areas can be beneficial in the prevention of cross-contamination by removing

particulate material from the soles of shoes or wheels. Windows/viewing

panels should be non-opening, encased, and flush with the wall panels and

appropriately sealed to prevent collection of dust and microbial matter.




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2.2.2. Drainage

• As drains are a potential source of contamination, they should be minimized.

• Where used, they should be

Hygienically designed to reduce the risk of aerosols, standing water and splash

back.

•

Drain covers, surfaces and joints should be:

Smooth and appropriate containment features should be incorporated within the

design.

• Water from any process system must have:

An ‘air break’ into a tundish before it is piped away – conventionally to a floor

drain.

• The floor drain will be trapped but there is still potential for the water in the drain to

be contaminated. The floor drain should be connected via a break tank (as minimum)

to the foul drain system. Although it does allow for the containment of contaminated

spillage (preventing it reaching the local foul system), the primary purpose of the

break tank is to prevent any backflow of contaminated waste from the foul drain into

the process drainage system.

• Drains is required to be

Disinfected on a regular basis upon a known understanding of the microbial

contamination risk presented because drains are the primary link between the

room and the external drainage system

2.2.3. Heating, Ventilation and Air Conditioning (HVAC) System

• Humidity control is key for some storage areas if materials are hygroscopic, increased

moisture levels may present a risk to microbial proliferation.

• Air ‘quality’ is improved by filtering the air through progressively more efficient filter

media.

1. Higher risk activities are recommended through the industry to use

Absolute filtration, using High Efficiency Particulate Air (HEPA) filters

removing 99.97% of particles sized greater than 0.3μm

2. However, in lower risk activities e.g. tablet manufacture less efficient

filters, e.g. bag filters removing 90% of particles sized greater than

0.5μm, with turbulent air flow are sufficient.

Current industry practice is to have:

1- Pressure differentials of 10 –20 Pa between areas of different standards.

2- Air changes for lower risk activities typically 10 –15 per hour.

Air changes rates for higher risk activities are higher, typically greater than 20 per

hour.

3- An appropriate Operational practices. For example, where a processing room is

at negative pressure to a corridor for the containment of active ingredients, there is an

increased risk of microbial ingress from the corridor. Consequently, an effective

cleaning regime for the corridor is required to ensure that microbial levels are kept

low.




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• Table of different standards for air classification

EU GMP

Annex 1 2008 At rest

ISO 14644

1999 pt1

US federal

Standard 209E Withdrawn

0.5μm

Particles/m3

5μm

Particles/m3

A-B 5 100 3520 Grade A=20

Grade B= 29

C 7 10000 352000 2900

D 8 100000 3520000 29000

2.3. Utilities

2.3.1. Compressed gases:

• Filtered at end of use and measuring differential pressure before and after the filter.

2.3.2. Water

2.3.2.1 Potable Water

• Potable water may be used for hand washing and initial cleaning or wash-in-

place systems.

2.3.2.2 Purified water:

• Purified water is generated from potable water, e.g. by

1.

Reverse osmosis or

2.

Distillation, though the latter is typically only used for the generation

of WFI

• Where process water is treated by the manufacturer to create the

appropriate quality, the treatment process should be validated and

routinely monitored.

• Incoming water should be sampled at point of entry on a routine basis.

• Piped purified water systems are typically monitored

1.

Continually on-line for conductivity and Total Organic Carbon (TOC)

2.

Routinely for chemical and microbial quality.

• Most microbial problems arise from the storage and distribution of the

water rather than its generation – the development of biofilms can be extremely

difficult to resolve.

• However, improperly maintained generation components, e.g. carbon beds,

softeners, reverse osmosis membranes, can also contribute to subsequent

contamination downstream within the distribution system.




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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






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- Formulation

Risk management during manufacturing

• Important factors to consider in the

manufacturing process include:

5.1. Processing steps

5.1.1 Solvents used:

• Water-based processes provide a more

favorable environment for

microorganisms

• The use of other solvents might decrease the risk of microbial growth.

5.1.2 Temperatures used:

• 25 –35°C promoting microbial growth.

• Significantly higher or lower temperatures being detrimental ض to micro-organisms

5.1.3 Hold times and overall campaign length:

• Longer processing times may increase the opportunity for microbial proliferation

unless the conditions are detrimentalض

to microbial growth

• Processes requiring heavy physical labor or increased numbers of personnel might

increase the risk of contamination from personnel through enhanced sweating or

shedding of skin particles.

• Water is a frequently used material and there needs to be assurance of the quality of

water used.

• Product-contact utilities, such as compressed air and Nitrogen, must not be forgotten.

These will typically be filtered close to the point of use.

5.1.4 Drying: • If the water activity of the product is reduced below 0.6, then microbial growth will be

suppressed.

5.2. pH:

• Values > 10 or < 2 generally being detrimentalض

to micro-organisms

5.3. Osmolarity of solutions:

• High osmolarity typically being detrimental toض

micro-organisms

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GMP Requirement to Control Microbial Contamination in Non Sterile Products

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