Transcript GMP Inspection Process

Basic Principles of GMP
WHO good practices
for
pharmaceutical
microbiology laboratories
Part 1
TRS 961, 2011. Annex 2
Module 14 |
Slide 1 of 40
2013
Microbiology Laboratories
 Personnel
 Environment
–
–
–
–
Premises
Environmental monitoring in the laboratory
Cleaning, disinfection and hygiene
Sterility test facilities
 Validation of test methods
 Equipment
– Maintenance of equipment
– Qualification
– Calibration, performance verification and monitoring of use
Module 14 |
Slide 2 of 40
2013
Microbiology Laboratories
 Reagents and culture media
–
–
–
–
Reagents
Media
Labelling
Organism resuscitation
 Reference materials and reference cultures
– International standards and pharmacopoeial reference substances
– Reference cultures
 Sampling
 Sample handling and identification
Module 14 |
Slide 3 of 40
2013
Microbiology Laboratories
 Disposal of contaminated waste
 Quality assurance of results and quality control of performance
– Internal quality control
 Testing procedures
 Test reports
Module 14 |
Slide 4 of 40
2013
Microbiology Laboratories
Introduction and scope of document
 Some of the activities in pharmaceutical microbiology laboratories
include:
– sterility testing;
– detection, isolation, enumeration and identification of microorganisms
(bacteria, yeast and moulds) and testing for bacterial endotoxins in
different materials (e.g. starting materials, water), products, surfaces,
garments and the environment; and
– assay using microorganisms as part of the test system.
 The WHO guidelines cover recommendations for these activities
 See also other guidelines and pharmacopoeia
Module 14 |
Slide 5 of 40
2013
Microbiology Laboratories
Personnel
Module 14 |
Slide 6 of 40
2013
Microbiology Laboratories
Personnel
 Testing and supervision by experienced persons, qualified in
microbiology or equivalent field
 Training in microbiology and relevant practical experience
 Current job descriptions for all personnel involved in tests and/or
calibrations, validations and verifications should be maintained.
 Records of all technical personnel, describing their qualifications,
training and experience.
 Opinions and interpretations of test results by authorized
personnel with suitable experience and relevant knowledge
Module 14 |
Slide 7 of 40
2013
1.1 – 1.3
Microbiology Laboratories
 All personnel to have adequate training e.g.
– performance of tests
– operation of equipment
– basic techniques, e.g. plate pouring, counting of colonies, aseptic
technique, media preparation, serial dilutions, and basic techniques in
identification
 Trained for containment of microorganisms within the laboratory
 Trained in safe handling of microorganisms
 Competence monitored - retraining where necessary
1.4 – 1.6
Module 14 |
Slide 8 of 40
2013
Microbiology Laboratories
 There should be restricted access to the microbiological
laboratory
 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
2.1.5
Module 14 |
Slide 9 of 40
2013
Microbiology Laboratories
Environment
Premises
Module 14 |
Slide 10 of 40
2013
Microbiology Laboratories
 Dedicated and separated: areas and support equipment (e.g.
autoclaves and glassware)
 Appropriate design for operations, sufficient space, avoid mix ups,
contamination and cross-contamination
 Suitable materials of construction to enable appropriate cleaning,
disinfection and minimize the risks of contamination
 Space for samples, reference organisms, media (if necessary,
with cooling), testing and records. Separate storage locations for
some media/samples
2.1.1. – 2.1.3.
Module 14 |
Slide 11 of 40
2013
Microbiology Laboratories
 Separate air supply to laboratories and production areas with
temperature and humidity control
 Appropriate quality of air - not to be a source of contamination
 Segregated, classified areas for sample preparation, media and
equipment preparation and enumeration of microorganisms
 Non-dedicated areas can be used based on risk management
principles should be applied
2.1.4 – 2.1.6
Module 14 |
Slide 12 of 40
2013
Microbiology Laboratories
 Classification should be based on criticality
 Sterility testing should always be performed in a dedicated area
 Equipment not moved between areas of different cleanliness
class, and not be used outside the microbiology area, unless
there are specific precautions in place to prevent crosscontamination
2.1.6 - 2.1.8
Module 14 |
Slide 13 of 40
2013
Microbiology Laboratories
Environmental monitoring in the laboratory
 Environmental monitoring programme where necessary e.g. in
areas for sterility testing
– Active air monitoring, air settling or contact plates, temperature and
pressure differentials.
– Alert and action limits; and trending of results
Cleaning, disinfection and hygiene
 Cleaning and disinfection programme with results
 SOP for dealing with spillages.
 Hand-washing and hand-disinfection facilities
Module 14 |
Slide 14 of 40
2013
2.2.1 – 2.3.3
Microbiology Laboratories
Sterility test facilities
 Specific environmental requirements - clean-room requirements
 Done under aseptic conditions
 Class A (ISO 4.8) in Class B background (unidirectional airflow) or within a barrier isolator/biosafety cabinet
 Suitable design of the facility layout and room airflow patterns, to
ensure that the unidirectional airflow patterns are not disrupted.
 Premises, services and equipment subjected to the appropriate
qualification process
2.4.1 – 2.4.3

Module 14 |
Slide 15 of 40
2013
Microbiology Laboratories
Module 14 |
Slide 16 of 40
2013
Microbiology Laboratories
 Clean-room classification and air-handling equipment of the
sterility test facilities should be requalified at least annually (or
other frequency if no risk). Tests should include e.g.:
– Non-viable and viable limits
– HEPA filter integrity
– Room airflows
 SOPs to state mapping locations for sample points for routine
monitoring, exposure duration, and frequency of all types of
microbiological environmental monitoring
 Garments appropriate, and operators trained and certified in
gowning procedures
2.4.4, 2.4.9
Module 14 |
Slide 17 of 40
2013
Microbiology Laboratories
 Grade A and B zones – supplied with terminal HEPA filters.
 Airflow alarms and pressure differentials and indication
instruments
 Room pressure readings taken and recorded
 Pressure gauges should be labelled to indicate the area served
and the acceptable specification.
 Entry to the clean rooms via airlocks, suitable size
 Final change room should be under “at rest” conditions of the
same grade as the room it serves
2.4.5 – 2.4.8
Module 14 |
Slide 18 of 40
2013
Microbiology Laboratories
 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.
Module 14 |
Slide 19 of 40
2013
2.4.11
Microbiology Laboratories
Module 14 |
Slide 20 of 40
2013
Microbiology Laboratories
Microbial environmental monitoring of the sterility test zone:
 during every work session
 under operational (dynamic) conditions
 written specifications
 alert and action limits for microbial contamination
2.4.11
Module 14 |
Slide 21 of 40
2013
Microbiology Laboratories
Validation of test methods
 Compendial methods: Need to be shown to be suitable for use in
recovering bacteria, yeast and mould in the presence of the
specific product. Method verification needed and test method
suitability including positive and negative controls
 Non compendial or other recognized references: Validated before
use and include e.g. accuracy, precision, specificity, limit of
detection, limit of quantitation, linearity and robustness
 Potentially inhibitory effects considered
3.1 – 3.2
 Appropriate statistical methods used (see pharmacopoeias)
Module 14 |
Slide 22 of 40
2013
Microbiology Laboratories
Equipment
 Each item of equipment, instrument or other device used for
testing, verification and calibration should be uniquely identified
 Documented programme for the qualification, calibration,
performance verification, maintenance
 System for monitoring the use of its equipment.
 SOP for maintenance of essential equipment at predetermined
intervals
 Detailed records kept
Module 14 |
Slide 23 of 40
2013
4.1
Microbiology Laboratories
Qualification
 For qualification of equipment see details in the training modules
on Good practices for pharmaceutical quality control laboratories
 DQ
 IQ
 OQ
 PQ
4.2
Module 14 |
Slide 24 of 40
2013
Microbiology Laboratories
Calibration, performance verification and monitoring of
use
 Instruments labelled (dates)
 Frequency of calibration and performance verification
determined
 Intervals between calibration and verification should be
shorter than the time the equipment has been found to take
to drift outside acceptable limits
4.3.1 – 4.3.3
 Equipment to perform to predefined acceptance criteria
Module 14 |
Slide 25 of 40
2013
Microbiology Laboratories
Examples of maintenance of equipment
 The next two slides provide information as examples
 The frequency should be based on the need, type and previous
performance of the equipment and on the recommendations in
suppliers’ manuals
Module 14 |
Slide 26 of 40
2013
Microbiology Laboratories
Type of equipment
— Incubators
— Fridges
— Freezers, ovens
Requirement
Clean and disinfect
surfaces
Suggested frequency
internal — Monthly
— When required (e.g. every 3
months)
— When required (e.g. annually)
Empty, clean, disinfect and refi ll — Monthly, or every 6 months if
biocide used
— Service
— Annually
— Clean and disinfect
— Each use
— Make visual checks of gasket, — Regularly, as recommended by
clean/drain chamber
manufacturer
— Full service
— Annually or as recommended
— Safety checkf pressure vessel by manufacturer
— Annually
Water-baths
Centrifuges
Autoclaves
Safety cabinets
cabinets
Microscopes
Module 14 |
unidirectional Full service and mechanical Annually or as recommended by
check
manufacturer
Full maintenance service
Annually
Slide 27 of 40
2013
Microbiology Laboratories
Type of equipment
pH meters
Balances, gravimetric diluters
Stills
De-ionizers, reverse
osmosis units
Anaerobic jars
Media dispensers, volumetric
equipment, pipettes and general
service equipment
Spiral platers
Laboratory
Module 14 |
Slide 28 of 40
2013
Requirement
Clean electrode
— Clean
— Service
Clean and de-scale
Replace cartridge/
membrane
Clean/disinfect
Decontaminate,
clean
sterilize as appropriate
Suggested frequency
Each use
— Each use
— Annually
As required (e.g. every 3 months)
As
recommended
manufacturer
After each use
and Each use
— Service
— Annually
— Decontaminate, clean and — Each use
sterlize
— Clean and disinfect
— Daily and during use
working surfaces
— Daily
— Clean floors, disinfect
— Every 3 months
by
Microbiology Laboratories
Type of equipment
Reference
thermometers
(liquid-in-glass)
Requirement
Full traceable recalibration
Suggested frequency
Every 3 years
Single point
(e.g. ice-point check)
Annually
Reference
thermocouples
Every 3 years
Annually
Full traceable recalibration
Check
against
reference
thermometer
Working thermometers and Check
against
reference
working thermocouples
thermometer
at ice-point and/or working
temperature range
Balances
Full traceable calibration
Volumetric
Gravimetric calibration to
glassware
required
tolerance
Module 14 |
Slide 29 of 40
2013
Annually
Annually
Annually
Microbiology Laboratories
Examples of equipment qualification and monitoring
 This information is provided as an example and the frequency will
be based on the need, type, previous performance and criticality
of the equipment.
Module 14 |
Slide 30 of 40
2013
Microbiology Laboratories
Temperature-controlled equipment (incubators, baths, fridges, freezers)
Establish stability and uniformity Initially, every 2 years and after
of temperature
repair/modification
Monitor temperature
Daily/each use
Sterilizing ovens
Establish stability and
uniformity of temperature
Initially, every 2 years and after
repair/modification
Monitor temperature
Each use
Module 14 |
Slide 31 of 40
2013
Microbiology Laboratories
Type of equipment Requirement Suggested frequency
Autoclaves
Establish characteristics for
loads/cycles
Initially, every 2 years and after
repair/modification
Monitor
temperature/pressure/time
Each use
Module 14 |
Slide 32 of 40
2013
Microbiology Laboratories
Isolators
Establish performance
Initially, every year and after
repair/modification
Microbiological monitoring
Each use
Airflow monitoring
6 monthly
Test for integrity of HEPA
filters
6 monthly
Module 14 |
Slide 33 of 40
2013
Microbiology Laboratories
Temperature measurement devices
 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
4.3.3
Module 14 |
Slide 34 of 40
2013
Microbiology Laboratories
Module 14 |
Slide 35 of 40
2013
Microbiology Laboratories
Incubators, water-baths and ovens
 The stability of temperature, uniformity of temperature distribution,
time required to achieve equilibrium conditions in incubators,
water-baths, ovens and temperature-controlled rooms should be
established initially and documented, in particular with respect to
typical uses (for example, position, space between, and height of,
stacks of Petri dishes)
 Recorded during initial validation, checked and recorded after
each significant repair or modification
 Operating temperature of this type of equipment should be
monitored and records retained
Module 14 |
Slide 36 of 40
2013
4.3.4
Microbiology Laboratories
Autoclaves, including media preparators
 Autoclaves to meet specified time and temperature tolerances as
well as pressure
 Sensors used calibrated and timers verified
 Validation to include temperature distribution studies for each
operating cycle and each load configuration used; and heat
penetration studies
 In the case of media preparators – use two sensors
 Validation and revalidation should consider heating, sterilisation
4.3.5
and cooling
Module 14 |
Slide 37 of 40
2013
Microbiology Laboratories
 Clear operating instructions (SOPs)
 Acceptance/rejection criteria
 Records of autoclave operations, including temperature and time,
maintained for every cycle
 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.
 Use of chemical or biological indicators and autoclave tape
 Separate autoclave for decontamination
Module 14 |
Slide 38 of 40
2013
4.3.5
Microbiology Laboratories
Weights and balances
 Regular calibration, traceable to standard weights and certified
standard weights
Volumetric equipment
 Initial verification of volumetric equipment (automatic dispensers,
dispenser/diluters, mechanical hand pipettes and disposable
pipettes) - then regular checks thereafter
4.3.6 – 4.3.7
 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 - “single-use” also checked
Module 14 |
Slide 39 of 40
2013
Microbiology Laboratories
Other equipment
 Conductivity meters, oxygen meters, pH meters and other similar
instruments verified regularly or before each use
 Buffers used - storage and expiry dated
 Where hygrometers are used – calibrated
 Timers verified using a calibrated timer or national time signal
 Centrifuges – verify rotations per minute (RPM). Where it is
critical, the centrifuge should be calibrated
4.3.8
Module 14 |
Slide 40 of 40
2013