WHO Good Practices for Microbiology Labs.

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 This presentation is compiled from freely
available resources
 like the website of WHO and specifically WHO
Guidance on Good Practices for Pharmaceutical
Microbiological Laboratories.
 “Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
 Visit http://www.drugregulations.org for latest
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Drug Regulations : Online
Resource for Latest Information

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 The WHO in 2009 published Good practices
for pharmaceutical quality control
laboratories.
 When this guide was used to inspect Labs
the inspectors realized the need for a
separate guideline for Microbial labs
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 The Expert Committee then recommended
developing a new text on good practices for
pharmaceutical microbiology laboratories.
 This was published as Annex 2 in WHO TRS
No. 961 in 2011.
 This presentation summarizes this guidance
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 These guidelines relate to all microbiology
laboratories involved in testing activities
◦ Independent labs
◦ Department or unit of a pharmaceutical
manufacturing facility
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 These guidelines are based on and supplement the
requirements described in
1. Good practices for pharmaceutical quality control
laboratories
2. General guidelines for the establishment, maintenance and
distribution of chemical reference substances.
3. The International Pharmacopoeia, Fourth Edition
4. First Supplement to The International Pharmacopoeia, Fourth
Edition
5. ISO/IEC 17025
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 Pharmaceutical microbiology laboratories may be
involved in:
◦ Sterility testing;
◦ Detection, isolation, enumeration and identification of
microorganisms
 (bacteria, yeast and moulds)
◦ Testing for bacterial endotoxins in different materials
 (e.g. starting materials, water), products, surfaces, garments and
the environment;
◦ Assay using microorganisms
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 Microbiological testing
◦ Should be performed and supervised by an experienced
person only.
◦ Personnel should be qualified in microbiology or
equivalent.
◦ They should have basic training in microbiology
◦ They should have relevant practical experience
before commencing testing.
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 Current job descriptions for all personnel
should be maintained.
◦ Personnel involved in tests and/ or calibrations,
validations and verifications
 The laboratory should also maintain records of
all technical personnel
 These should describe their qualifications,
training and experience.
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 If test results in reports have opinions and
interpretations, this should be done by
authorized personnel
 These personnel should have suitable
experience and relevant knowledge of the
specific application
 This can include regulatory and technological
requirements and acceptability criteria.
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 The laboratory management should ensure that all personnel have
received adequate training for
◦ Competent performance of tests and
◦ Operation of equipment.
 This should include training in
◦ Basic techniques, e.g. plate pouring, counting of colonies, aseptic technique,
media preparation, serial dilutions, and
◦ Basic techniques in identification
 The acceptability of training should be determined using objective
criteria where relevant.
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 Only competent personnel should perform tests on samples.
 Otherwise testing should be done under adequate
supervision.
 Competence should be monitored continuously with provision
for retraining where necessary.
 Where a method or technique is not in regular use, the
competency of the personnel to perform the test should be
verified before testing is undertaken.
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 In some cases it is acceptable to relate competence to a
general technique or instrument being used rather than to
particular methods.
 Personnel should be trained in necessary procedures for
containment of microorganisms within the laboratory facility.
 Personnel should be trained in safe handling of
microorganisms.
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 Microbiology laboratories should be dedicated and separated
from other areas, especially from production areas.
 Similarly certain support equipment (e.g. autoclaves and
glassware) should be dedicated.
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 Microbiology laboratories should be designed to suit the
operations to be carried out in them.
 There should be sufficient space for all activities to avoid mix
ups, contamination and cross-contamination.
 There should be adequate suitable space for samples,
reference organisms, media (if necessary, with cooling),
testing and records.
 Due to the nature of some materials (e.g. sterile media versus
reference organisms or incubated cultures), separate storage
locations may be necessary.
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 Laboratories should be appropriately
designed.
 They should take into account the
suitability of construction materials to
enable appropriate cleaning, disinfection
and minimize the risks of contamination.
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 There should be separate air supply to laboratories
and production areas.
 Separate air-handling units and other provisions,
including temperature and humidity controls where
required, should be in place for microbiological
laboratories.
 The air supplied to the laboratory should be of
appropriate quality and should not be a source of
contamination.
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 Access to the microbiological laboratory should be
restricted to authorized personnel.
 Personnel should be made aware of:
◦ The appropriate entry and exit procedures including
gowning; — the intended use of a particular area;
◦ The restrictions imposed on working within such areas;
◦ The reasons for imposing such restrictions; and
◦ The appropriate containment levels
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 Laboratory activities, such as sample preparation, media and
equipment preparation and enumeration of microorganisms,
should be segregated by space or at least in time.
 This minimizes risks of cross- contamination, false-positive
results and false-negative results.
 Where non- dedicated areas are used, risk management
principles should be applied.
 Sterility testing should always be performed in a dedicated
area.
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 Consideration should be given to designing appropriate
classified areas for the operations to be performed within the
microbiology laboratory.
 The classification should be based on the criticality of the
product and the operation being carried out in the area.
 Sterility testing should be performed under the same class as
used for sterile/aseptic manufacturing operations.
 Appendix 1 shows recommendations for zone classifications.
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 In general, laboratory equipment should not routinely be
moved between areas of different cleanliness class, to avoid
accidental cross- contamination.
 Laboratory equipment used in the microbiology laboratory
should not be used outside the microbiology area, unless
there are specific precautions in place to prevent cross-
contamination.
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 Where necessary and appropriate (e.g. in areas for sterility
testing) an environmental monitoring programme should be
in place
 This should cover for example, use of active air monitoring,
air settling or contact plates, temperature and pressure
differentials.
 Alert and action limits should be defined.
 Trending of environmental monitoring results should be
carried out.
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 There should be a documented cleaning and disinfection
programme.
 Results of environmental monitoring should be considered
where relevant.
 There should be a procedure for dealing with spillages.
 Adequate hand-washing and hand-disinfection facilities
should be available.
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 Sterility test facilities have specific environmental
requirements to ensure the integrity of tests carried out.
 WHO good manufacturing practices (GMP) for sterile
pharmaceutical products requires that sterility testing should
be carried out and specifies requirements for sterility testing.
 This section details the clean-room requirements for a
sterility test facility.
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 Sterility testing should be performed under aseptic
conditions,
 These should be equivalent to air quality standards required
for the aseptic manufacture of pharmaceutical products.
 The premises, services and equipment should be subject to
the appropriate qualification process.
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 The sterility testing should be carried out within a Grade A
unidirectional airflow protected zone or a biosafety cabinet (if
warranted), which should be located within a clean room with
a Grade B background.
 Alternatively, the testing can be carried out within a barrier
isolator.
 Care should be taken with the design of the facility layout and
room airflow patterns, to ensure that the unidirectional
airflow patterns are not disrupted.
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 The clean-room classification and air-handling equipment of
the sterility test facilities should be requalified at least
annually by a competent person or contractor.
 The environment should comply with the non-viable and
viable limits,
 Verification of high efficiency particulate air (HEPA) filter
integrity and room airflows should be performed.
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 However, an alternative frequency of the monitoring may be
justified based on quality risk management (QRM).
 Mapping locations for sample points for routine monitoring
should be documented,
 Exposure duration, and frequency of all types of
microbiological environmental monitoring should be specified
in written procedures.
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 Air supplied to Grade A and B zones should be via terminal HEPA
filters.
 Appropriate airflow alarms and pressure differentials and
indication instruments should be provided
 Room pressure readings should be taken and recorded from
externally mounted gauges unless a validated continuous
monitoring system is installed.
 As a minimum, readings should be taken prior to entry of the
operator to the test suite.
 Pressure gauges should be labelled to indicate the area served
and the acceptable specification.
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 Entry to the clean room should be via a system of airlocks and a
change room where operators are required to don suitable clean-
room garments.
 The final change room should be under “at rest” conditions of the
same grade as the room it serves.
 Change rooms should be of adequate size for ease of changing.
There should be clear demarcation of the different zones.
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 Garments for the sterility test operator should comply with
the principles of section 10 of WHO GMP for sterile
pharmaceutical products
 Operators should be trained and certified in gowning
procedures with training records maintained.
 The fittings and finishes of the premises should comply with
section 11 of WHO GMP for sterile pharmaceutical products
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 Environmental microbiological monitoring should reflect the
facility used (room or isolator) and include a combination of
air and surface sampling methods appropriate to the facility,
such as:
 Active air sampling;
 Settle (exposure) plates;
 Surface contact — replicate organism detection and counting
(RODAC) plates, swabs or flexible films;
 Operators’ glove prints.
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 Microbial environmental monitoring of the sterility test zone
should be performed during every work session under
operational (dynamic) conditions.
 There should be written specifications, including appropriate
alert and action limits for microbial contamination.
 Limits for microbiological environmental monitoring are given
in the WHO GMP for sterile pharmaceutical products
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 Standard (pharmacopoeial) test methods are
considered to be validated.
 However, the specific test method to be used by
a specific laboratory for testing of a specific
product needs to be shown to be suitable for use
 This is for recovering bacteria, yeast and mould
in the presence of the specific product.
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 The laboratory should demonstrate
◦ That the performance criteria of the standard test
method can be met by the laboratory before introducing
the test for routine purposes
 (method verification) and
◦ That the specific test method for the specific product is
suitable
 (test method suitability including positive and negative
controls).
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 Test methods not based on compendial or other recognized
references should be validated before use.
 The validation should comprise, determining
◦ Accuracy
◦ Precision
◦ Specificity
◦ Limit of detection
◦ Limit of quantitation
◦ Linearity
◦ Robustness.
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 Potentially inhibitory effects from the sample
should be taken into account
 The results should be evaluated with
appropriate statistical methods as described
in National Pharmacopoeias.
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 Each item of equipment, instrument or other device used
for testing, verification and calibration should be uniquely
identified.
 As part of its quality system, a laboratory should have a
documented programme for the
◦ Qualification
◦ Calibration
◦ Performance verification
◦ Maintenance
◦ System for monitoring the use of its equipment
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 Maintenance of essential equipment should
be carried out at predetermined intervals
 This should be in accordance with a
documented procedure.
 Detailed records should be kept.
 For examples of maintenance of equipment
and intervals see Appendix 2.
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 All equipment should be qualified
 Refer Good practices for pharmaceutical
quality control laboratories
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 Calibration, performance verification and monitoring of
use
 The date of calibration and servicing and the date when
recalibration is due should be clearly indicated on a label
attached to the instrument.
 The frequency of calibration and performance verification
◦ Will be determined by documented experience and
◦ Will be based on need, type and previous performance of the
equipment.
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 Intervals between calibration and verification should
be shorter than the time the equipment has been
found to take to drift outside acceptable limits.
◦ For examples of calibration checks and intervals for
different laboratory equipment, see Appendix 3;
◦ and for equipment qualification and monitoring, see
Appendix 4.
 The performance of the equipment should conform to
predefined acceptance criteria.
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 Where temperature has a direct effect on the result of an
analysis or is critical for the correct performance of
equipment, temperature measuring devices should be of
appropriate quality to achieve the accuracy required
◦ e.g. liquid-in-glass thermometers, thermocouples and platinum
resistance thermometers (PRTs) used in incubators and
autoclaves.
 Calibration of devices should be traceable to national or
international standards for temperature.
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 The stability of temperature, uniformity of
temperature distribution and time required to achieve
equilibrium conditions in incubators, water-baths,
ovens and temperature-controlled rooms should be
established initially and documented,
 This should be particularly with respect to typical
uses
◦ for example, position, space between, and height of, stacks
of Petri dishes
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 The constancy of the characteristics recorded during
initial validation of the equipment should be checked
and recorded after each significant repair or
modification.
 The operating temperature of this type of equipment
should be monitored and records retained.
 The use of the equipment should be considered when
determining what temperature controls are required.
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 Autoclaves should be capable of meeting
specified time and temperature tolerances;
 Monitoring pressure alone is not acceptable.
 Sensors used for controlling or monitoring
operating cycles require calibration
 The performance of timers should be verified.
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 Initial validation should include performance studies
(spatial temperature distribution surveys) for each
operating cycle and each load configuration used in
practice.
 This process must be repeated after any significant repair
or modification
◦ Replacement of the probe or programmer
◦ Change to loading arrangements or operating cycle or
◦ Where indicated by the results of quality control checks on media
or risk assessment.
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 Sufficient temperature sensors should be positioned within the load
 (e.g. in containers filled with liquid/medium) to enable location
differences to be demonstrated.
 In the case of media preparators, where uniform heating cannot be
demonstrated by other means, the use of two sensors, one adjacent to
the control probe and one remote from it, would generally be considered
appropriate.
 Validation and revalidation should consider the suitability of come-up
and come-down times as well as time at sterilization temperature.
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 Clear operating instructions should be provided
based on the heating profiles determined for
typical uses during validation/revalidation.
 Acceptance/rejection criteria should be
established and records of autoclave operations,
including temperature and time, maintained for
every cycle.
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 Monitoring may be achieved by one of the
following:
◦ Using a thermocouple and recorder to produce a
chart or printout;
◦ Direct observation and recording of maximum
temperature achieved and time at that temperature.
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 In addition to directly monitoring the temperature of an
autoclave, the effectiveness of its operation during each
cycle may be checked by the use of chemical or biological
indicators for sterilization or decontamination purposes.
 Autoclave tape or indicator strips should be used only to
show that a load has been processed, not to demonstrate
completion of an acceptable cycle.
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 Laboratories should have a separate autoclave for
decontamination.
 However, in exceptional cases one autoclave may
be acceptable provided that
◦ Extensive precautions are taken to separate
decontamination and sterilization loads, and
◦ A documented cleaning programme is in place to
address both the internal and external environment of
the autoclave.
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 Weights and balances shall be calibrated
traceably at regular intervals (according to
their intended use) using appropriate
standard weights traceable to certified
standard weights.
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 Microbiology laboratories should carry out initial verification of volumetric
equipment
◦ (automatic dispensers, dispenser/diluters, mechanical hand pipettes and disposable
pipettes)
 Then make regular checks, as appropriate, to ensure that the equipment is
performing within the required specification.
 Initial verification should not be necessary for glassware which has been certified
to a specific tolerance.
 Equipment should be checked for the accuracy of the delivered volume against the
set volume
◦ for several different settings in the case of variable volume instruments) and
 The precision of the repeat deliveries should be measured.
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 For “single-use” disposable volumetric equipment,
laboratories should obtain supplies from companies
with a recognized and relevant quality system.
 After initial validation of the suitability of the
equipment, it is recommended that random checks
on accuracy are carried out.
 If the supplier does not have a recognized quality
system, laboratories should check each batch of
equipment for suitability.
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 Conductivity meters, oxygen meters, pH meters and other
similar instruments should be verified regularly or before
each use.
 The buffers used for verification purposes should be
stored in appropriate conditions and should be marked
with an expiry date.
 Where humidity is important to the outcome of the test,
hygrometers should be calibrated, the calibration being
traceable to national or international standards.
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 Timers, including the autoclave timer, should be
verified using a calibrated timer or national time
signal.
 When centrifuges are used in test procedures, an
assessment of the rotations per minute (RPM) should
be made.
 Where it is critical, the centrifuge should be
calibrated.
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 Laboratories should ensure that the quality of
reagents and media used is appropriate for
the test concerned.
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 Laboratories should verify the suitability of
each batch of reagents critical for the test,
initially and during its shelf-life.
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 Media may be prepared in-house or purchased either
partially or fully prepared.
 Vendors of purchased media should be approved and
qualified.
 The qualified vendor may certify some of the quality
parameters listed subsequently.
 Growth promotion and, if appropriate, other suitable
performance tests should be done on all media on
every batch and on every shipment.
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 Fully prepared media
◦ Supplier should be qualified
◦ Supplier should provide growth promotion
certification per batch of media
◦ Transportation conditions should be qualified
◦ User may rely on the manufacturer’s certificate with
periodic verification of his or her results.
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 The suitable performance of culture media, diluents and other
suspension fluids should be checked, where relevant, with regard to:
◦ Recovery or survival maintenance of target organisms.
◦ Recovery of 50–200% (after inoculation of not more than 100 colony-
forming units (CFU or cfu) should be demonstrated;
◦ Inhibition or suppression of non-target organisms;
◦ Biochemical (differential and diagnostic) properties; and
◦ Other appropriate properties (e.g. pH, volume and sterility)
◦ Quantitative procedures for evaluation of recovery or survival are
preferred.
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 Raw materials and media should be stored under
appropriate conditions recommended by the
manufacturer,
◦ e.g. cool, dry and dark.
 Applicable to both commercial dehydrated formulations
and individual constituents)
 All containers, especially those for dehydrated media,
should be sealed tightly.
 Dehydrated media that are caked or cracked or show a
colour change should not be used.
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 Water of a suitable microbiological quality should be used for
preparation unless the test method specifies otherwise.
◦ e.g. which is free from bactericidal, inhibitory or interfering substances
 Media containing antimetabolites or inhibitors should be prepared using
dedicated glassware.
 Carry-over of these agents into other media could inhibit the growth
and detection of microorganisms present in the sample under test.
 If dedicated glassware is not used, washing procedures for glassware
should be validated.
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 Repartition of media after sterilization should be
performed under unidirectional airflow (UDAF) to
minimize potential for environmental contamination.
 This should be considered a minimum requirement
for media to be used in relation to sterile product
testing.
 This includes the cooling of media, as container lids
will need to be removed during cooling to prevent
build-up of condensation.
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 Plated media which is to be irradiated may require the
addition of an antioxidant and free radical scavenger
 This provides protection from the effects of the
irradiation process.
 The irradiated media should be validated by
performing quantitative growth promotion testing on
both irradiated and non-irradiated media.
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 Shelf-life of prepared media under defined storage
conditions shall be determined and verified.
 Batches of media should be identifiable and their
conformance with quality specifications documented.
 Any changes to the quality specification of purchased
media should be notified by the manufacturer to the
user
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 Media should be prepared in accordance with any
manufacturer’s instructions,
 This should take into account specifications such
as time and temperature for sterilization.
 Microwave devices should not be used for the
melting of media
 This is due to the inconsistent distribution of the
heating process.
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 Laboratories should ensure that all reagents (including
stock solutions), media, diluents and other suspending
fluids are adequately labelled to indicate, as appropriate,
◦ Identity
◦ Concentration
◦ Storage conditions
◦ Preparation date
◦ Validated expiry date and/or recommended storage periods
◦ The person responsible for preparation should be identifiable
from records.
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 Organism resuscitation is required where test
methodologies may produce sublethally injured
cells.
 For example, exposure to:
◦ Injurious effects of processing, e.g. heat; —
antimicrobial agents;
◦ Preservatives;
◦ Extremes of osmotic pressure; and
◦ Extremes of pH.
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 Organism resuscitation may be
achieved by:
◦ Exposure to a liquid media like a simple
salt solution at room temperature for 2
hours;
◦ Exposure to a solid repair medium for 4–6
hours.
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 Reference materials and certified reference
materials are generally used in a
microbiological laboratory to qualify, verify
and calibrate equipment.
 Whenever possible these reference materials
should be used in appropriate matrices.
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 International standards and pharmacopoeial
reference substances are employed, for
example, to:
◦ Determine potency or content; — validate methods;
◦ Enable comparison of methods; — perform positive
controls; and — perform growth promotion tests.
◦ If possible reference materials should be used in
appropriate matrices.
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 Reference cultures are required for
◦ Establishing acceptable performance of media
(including test kits),
◦ Validating methods,
◦ Verifying the suitability of test methods and
◦ Assessing or evaluating ongoing performance.
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 Traceability is necessary, for example, when establishing
media performance for test kit and method validations.
 To demonstrate traceability, laboratories must use
reference strains of microorganisms obtained directly from
a recognized national or international collection, where
these exist.
 Alternatively, commercial derivatives for which all relevant
properties have been shown by the laboratory to be
equivalent at the point of use may be used.
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 Reference strains may be subcultured once to provide reference stocks.
 Purity and biochemical checks should be made in parallel as appropriate.
 It is recommended to store reference stocks in aliquots either deep-
frozen or lyophilized.
 Working cultures for routine use should be primary subcultures from the
reference stock
 (see Appendix 5 on general use of reference cultures).
 If reference stocks have been thawed, they must not be refrozen and
reused.
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 Working stocks should not normally be subcultured.
 Usually not more than five generations (or passages) from
the original reference strain can be subcultured if defined
by a standard method
 Alternatively laboratories can provide documentary
evidence that there has been no change in any relevant
property.
 Commercial derivatives of reference strains may only be
used as working cultures.
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 Where testing laboratories are responsible for
primary sampling to obtain test items, this sampling
should be covered by a quality assurance system
 Sampling should be subject to regular audits.
 Any disinfection processes used in obtaining the
sample (e.g. disinfection of sample points) should not
compromise the microbial level within the sample.
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 Transport and storage of samples should be under conditions that maintain the
integrity of the sample (e.g. chilled or frozen where appropriate).
 Testing of the samples should be performed as soon as possible after sampling.
 For samples where a growth in the microbial population during transport and
storage is possible it should be demonstrated that the storage conditions, time
and temperature, will not affect the accuracy of the testing result.
 The storage conditions should be monitored and records kept.
 The responsibility for transport, storage between sampling and arrival at the
testing laboratory should be clearly documented.
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 Sampling should only be performed by trained personnel.
 It should be carried out aseptically using sterile equipment.
 Appropriate precautions should be taken to ensure that sample
integrity is maintained through the use of sterile sealed
containers for the collection of samples where appropriate.
 It may be necessary to monitor environmental conditions, for
example, air contamination and temperature, at the sampling
site.
 Time of sampling should be recorded, if appropriate.
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 The laboratory should have procedures that cover
the delivery and receipt of samples and sample
identification.
 Consult the client if
◦ There is insufficient sample
◦ The sample is in poor condition due to physical
deterioration, incorrect temperature, torn packaging
◦ The labeling is deficient
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 The laboratory should record all relevant
information, e.g.
◦ Date and, where relevant, the time of receipt;
◦ Condition of the sample on receipt and, when
necessary, temperature;
◦ Characteristics of the sampling operation including
sampling date and sampling conditions.
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 Samples awaiting testing should be stored under suitable conditions to
minimize changes to any microbial population present.
 Storage conditions should be validated, defined and recorded.
 The packaging and labels of samples may be highly contaminated
 They should be handled and stored with care so as to avoid any spread
of contamination.
 Disinfection processes applied to the outer container should not affect
the integrity of the sample.
 It should be noted that alcohol is not sporicidal.
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 Subsampling by the laboratory immediately prior to testing may be required as
part of the test method.
 It may be appropriate that it is performed according to national or international
standards, where they exist, or by validated in-house methods.
 Subsampling procedures should be designed to collect a representative sample.
 There should be a written procedure for the retention and disposal of samples.
 If sample integrity can be maintained it may be appropriate that samples are
stored until the test results are obtained, or longer if required.
 Laboratory sample portions that are known to be contaminated should be
decontaminated prior to being discarded
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 The procedures for the disposal of contaminated
materials should be designed to minimize the
possibility of contaminating the test environment
or materials.
 It is a matter of good laboratory management
and should conform to national/international
environmental or health and safety regulations.
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 The laboratory should have a system of internal
quality assurance or quality control to ensure the
consistency of results from day to day and their
conformity with defined criteria.
◦ Handling deviations
◦ Use of spiked samples
◦ Replicate testing and participation in proficiency testing
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 Testing should normally be performed according
to procedures described in the national, regional
and international pharmacopoeias.
 Alternative testing procedures may be used if
they are appropriately validated and equivalence
to official methods has been demonstrated.
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 If the result of the enumeration is negative, it should
be reported as “not detected for a defined unit” or
“less than the detection limit for a defined unit”.
 The result should not be given as “zero for a defined
unit” unless it is a regulatory requirement.
 Qualitative test results should be reported as
“detected/not detected in a defined quantity or
volume”.
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 They may also be expressed as “less than a
specified number of organisms for a defined
unit” where the specified number of organisms
exceeds the detection limit of the method and
this has been agreed with the client.
 In the raw data the result should not be given as
zero for a defined unit unless it is a regulatory
requirement.
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 A reported value of “0” may be used for data entry and
calculations or trend analysis in electronic databases
 Where an estimate of the uncertainty of the test result is
expressed on the test report, any limitations have to be
made clear to the client.
 Particularly if the estimate does not include the component
contributed by the distribution of microorganisms within
the sample
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 This presentation is compiled from freely
available resources
 like the website of WHO and specifically WHO
Guidance on Good Practices for Pharmaceutical
Microbiological Laboratories.
 “Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
 Visit http://www.drugregulations.org for latest
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Drug Regulations : Online
Resource for Latest Information

WHO Good Practices for Microbiology Labs.

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WHO Good Practices for Microbiology Labs.