module 14 | slide 1 of 40 2013 basic principles of gmp who good practices for pharmaceutical...
TRANSCRIPT
Module 14 | Slide 1 of 40 2013
Basic Principles of GMPBasic Principles of GMP
WHO good practices
for
pharmaceutical
microbiology laboratories
TRS 961, 2011. Annex 2
Part 1
Module 14 | Slide 2 of 40 2013
Microbiology LaboratoriesMicrobiology 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 3 of 40 2013
Microbiology LaboratoriesMicrobiology 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 4 of 40 2013
Microbiology LaboratoriesMicrobiology Laboratories
Disposal of contaminated waste
Quality assurance of results and quality control of performance– Internal quality control
Testing procedures
Test reports
Module 14 | Slide 5 of 40 2013
Microbiology LaboratoriesMicrobiology 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 7 of 40 2013
Microbiology LaboratoriesMicrobiology 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
1.1 – 1.3
Module 14 | Slide 8 of 40 2013
Microbiology LaboratoriesMicrobiology 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 9 of 40 2013
Microbiology LaboratoriesMicrobiology 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 10 of 40 2013
Microbiology LaboratoriesMicrobiology Laboratories
Environment
Premises
Module 14 | Slide 11 of 40 2013
Microbiology LaboratoriesMicrobiology 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 12 of 40 2013
Microbiology LaboratoriesMicrobiology 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 13 of 40 2013
Microbiology LaboratoriesMicrobiology 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 cross-contamination
2.1.6 - 2.1.8
Module 14 | Slide 14 of 40 2013
Microbiology LaboratoriesMicrobiology 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 2.2.1 – 2.3.3
Module 14 | Slide 15 of 40 2013
Microbiology LaboratoriesMicrobiology 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 17 of 40 2013
Microbiology LaboratoriesMicrobiology 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 18 of 40 2013
Microbiology LaboratoriesMicrobiology 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 19 of 40 2013
Microbiology LaboratoriesMicrobiology 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. 2.4.11
Module 14 | Slide 21 of 40 2013
Microbiology LaboratoriesMicrobiology 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 22 of 40 2013
Microbiology LaboratoriesMicrobiology 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
Appropriate statistical methods used (see pharmacopoeias)
3.1 – 3.2
Module 14 | Slide 23 of 40 2013
Microbiology LaboratoriesMicrobiology 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 4.1
Module 14 | Slide 24 of 40 2013
Microbiology LaboratoriesMicrobiology 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 25 of 40 2013
Microbiology LaboratoriesMicrobiology 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
Equipment to perform to predefined acceptance criteria
4.3.1 – 4.3.3
Module 14 | Slide 26 of 40 2013
Microbiology LaboratoriesMicrobiology 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 27 of 40 2013
Microbiology LaboratoriesMicrobiology Laboratories
Type of equipmentRequirementSuggested frequency— Incubators— Fridges— Freezers, ovens
Clean and disinfect internal surfaces
— Monthly— When required (e.g. every 3 months)— When required (e.g. annually)
Water-bathsEmpty, clean, disinfect and refi ll— Monthly, or every 6 months if biocide used
Centrifuges — Service— Clean and disinfect
— Annually— Each use
Autoclaves— Make visual checks of gasket, clean/drain chamber— Full service— Safety checkf pressure vessel
— Regularly, as recommended by manufacturer— Annually or as recommended by manufacturer— Annually
Safety cabinets unidirectional cabinets
Full service and mechanical check
Annually or as recommended by manufacturer
MicroscopesFull maintenance service Annually
Module 14 | Slide 28 of 40 2013
Microbiology LaboratoriesMicrobiology Laboratories
Type of equipmentRequirementSuggested frequencypH meters Clean electrodeEach useBalances, gravimetric diluters— Clean
— Service— Each use— Annually
StillsClean and de-scaleAs required (e.g. every 3
months)De-ionizers, reverseosmosis units
Replace cartridge/membrane
As recommended by manufacturer
Anaerobic jarsClean/disinfect After each useMedia dispensers, volumetric equipment, pipettes and general service equipment
Decontaminate, clean and sterilize as appropriate
Each use
Spiral platers — Service— Decontaminate, clean and sterlize
— Annually— Each use
Laboratory — Clean and disinfectworking surfaces— Clean floors, disinfect
— Daily and during use— Daily— Every 3 months
Module 14 | Slide 29 of 40 2013
Microbiology LaboratoriesMicrobiology Laboratories
Type of equipmentRequirement Suggested frequencyReferencethermometers(liquid-in-glass)
Full traceable recalibrationEvery 3 years
Single point(e.g. ice-point check)
Annually
Referencethermocouples
Full traceable recalibrationCheck against reference thermometer
Every 3 yearsAnnually
Working thermometers and working thermocouples
Check against reference thermometerat ice-point and/or workingtemperature range
Annually
BalancesFull traceable calibrationAnnuallyVolumetricglassware
Gravimetric calibration to requiredtolerance
Annually
Module 14 | Slide 30 of 40 2013
Microbiology LaboratoriesMicrobiology 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 31 of 40 2013
Microbiology LaboratoriesMicrobiology Laboratories
Temperature-controlled equipment (incubators, baths, fridges, freezers)
Sterilizing ovens
Establish stability and uniformity of temperature
Initially, every 2 years and after repair/modification
Monitor temperatureDaily/each use
Establish stability and uniformity of temperature
Initially, every 2 years and after repair/modification
Monitor temperatureEach use
Module 14 | Slide 32 of 40 2013
Microbiology LaboratoriesMicrobiology Laboratories
Type of equipment Requirement Suggested frequency
Autoclaves
Establish characteristics for loads/cycles
Initially, every 2 years and after repair/modification
Monitor temperature/pressure/timeEach use
Module 14 | Slide 33 of 40 2013
Microbiology LaboratoriesMicrobiology 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 34 of 40 2013
Microbiology LaboratoriesMicrobiology 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 36 of 40 2013
Microbiology LaboratoriesMicrobiology 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 4.3.4
Module 14 | Slide 37 of 40 2013
Microbiology LaboratoriesMicrobiology 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 and cooling 4.3.5
Module 14 | Slide 38 of 40 2013
Microbiology LaboratoriesMicrobiology 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 4.3.5
Module 14 | Slide 39 of 40 2013
Microbiology LaboratoriesMicrobiology 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
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
4.3.6 – 4.3.7
Module 14 | Slide 40 of 40 2013
Microbiology LaboratoriesMicrobiology 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