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Module 14 | Slide 1 of 40 2013 Basic Principles of GMP WHO good practices for pharmaceutical microbiology laboratories TRS 961, 2011. Annex 2 Part 1

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Basic Principles of GMP. WHO good practices for pharmaceutical microbiology laboratories. Part 1. TRS 961, 2011. Annex 2. Microbiology Laboratories. Personnel Environment Premises Environmental monitoring in the laboratory Cleaning, disinfection and hygiene - PowerPoint PPT Presentation

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Page 1: Basic Principles of GMP

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

Page 2: Basic Principles of GMP

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

Page 3: Basic Principles of GMP

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

Page 4: Basic Principles of GMP

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

Page 5: Basic Principles of GMP

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

Page 6: Basic Principles of GMP

Module 14 | Slide 6 of 40 2013

Microbiology LaboratoriesMicrobiology Laboratories

Personnel

Page 7: Basic Principles of GMP

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

Page 8: Basic Principles of GMP

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

Page 9: Basic Principles of GMP

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

Page 10: Basic Principles of GMP

Module 14 | Slide 10 of 40 2013

Microbiology LaboratoriesMicrobiology Laboratories

Environment

Premises

Page 11: Basic Principles of GMP

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.

Page 12: Basic Principles of GMP

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

Page 13: Basic Principles of GMP

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

Page 14: Basic Principles of GMP

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

Page 15: Basic Principles of GMP

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

Page 16: Basic Principles of GMP

Module 14 | Slide 16 of 40 2013

Microbiology LaboratoriesMicrobiology Laboratories

Page 17: Basic Principles of GMP

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

Page 18: Basic Principles of GMP

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

Page 19: Basic Principles of GMP

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

Page 20: Basic Principles of GMP

Module 14 | Slide 20 of 40 2013

Microbiology LaboratoriesMicrobiology Laboratories

Page 21: Basic Principles of GMP

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

Page 22: Basic Principles of GMP

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

Page 23: Basic Principles of GMP

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

Page 24: Basic Principles of GMP

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

Page 25: Basic Principles of GMP

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

Page 26: Basic Principles of GMP

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

Page 27: Basic Principles of GMP

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

Page 28: Basic Principles of GMP

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

Page 29: Basic Principles of GMP

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

Page 30: Basic Principles of GMP

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.

Page 31: Basic Principles of GMP

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

Page 32: Basic Principles of GMP

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

Page 33: Basic Principles of GMP

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

Page 34: Basic Principles of GMP

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

Page 35: Basic Principles of GMP

Module 14 | Slide 35 of 40 2013

Microbiology LaboratoriesMicrobiology Laboratories

Page 36: Basic Principles of GMP

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

Page 37: Basic Principles of GMP

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

Page 38: Basic Principles of GMP

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

Page 39: Basic Principles of GMP

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

Page 40: Basic Principles of GMP

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