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GMP Compliance Auditing of Non-sterile Quality Control Microbiology Laboratories
DONALD J. ENGLISH
SENIOR MANAGER – R&D MICROBIOLOGY
AVON PRODUCTS, INC.
SUFFERN, NEW YORK 10901
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Personnel Job Description
Organization
Training and Skills
2
Personnel – Job Descriptions Must contain the following:
Job title
Reporting title of the position’s immediate supervisor.
Key functional and relational responsibilities
A summary of the general nature and level of the position.
A list of duties or tasks that a position is responsible for conducting
needs to be clearly described.
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Personnel - Organization
Organizational Chart Organizational structure should be defined.
Adequate laboratory staffing should be present.
Organizational chart should show independence of each quality unit, such as quality assurance or
quality control.
Supervisors must have the education, training and experience to perform assigned
job functions.
Adequate number of properly trained personnel for the size of the organization.
Personnel – Organizational Charts
Needs to illustrate the reporting relationships within the Quality Control Microbiology Testing Laboratory, as well as, that within the Quality System.
Manager of Department
Preservative Challenge Testing Supervisor
Microbial Content Supervisor
Quality Control Director
Microbial Media and Count Diluent Preparation Supervisor
Technician TechnicianMicrobiologist MicrobiologistMicrobiologist Microbiologist
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Personnel – Training and Skills
Personnel should have skills based upon relevant training and experience acquired or combination thereof, that are appropriate to their responsibilities and activities.
Appropriate cGMP training should be provided on an annual basis.
Newly Recruited Personnel
Training should be appropriate to the duties assigned to them.
Training is an on-going process that is subject to regular updates.
Personnel – Training Records
Types of Training Conducted: GMP and GLP Training (e.g. Yearly frequency) Laboratory Training (Must be conducted at a periodic frequency). Standard Operating Procedures (e.g. Laboratory Equipment and Microbial Growth Media and
Count Diluent Preparation and Sterilization)
Microbial Test Methods
Microbial Content – Raw Ingredients and Finished Products
Preservative Challenge Testing
Environmental Sampling and Testing (e.g. Air, Compressed Air and Water).
Microbial Monitoring for Cleaning and Sanitization of Manufacturing Equipment
Performance Assessment or Proficiency Training Aseptic technique, conductance of a microbial test method, etc.
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Personnel - Responsibilities
All laboratory personnel should:
Know their position in the organizational structure.
Know their defined responsibilities and activities.
Have access to documents and comply with documents relevant to their particular responsibility.
Comply with personal hygiene standards.
Be encourage to report irregularities and other non-conformities.
Have adequate educational training and skills to perform assigned responsibilities and activities.
Microbiology Laboratory Design Prevent Accidential Microbial Contamination to Samples and Personnel:
Separate areas for conducting microbial analysis of samples and support functions such as sample login,
media preparation, sample preparation and storage of personnel belongings.
Surfaces should be nonporous, cleanable and sanitizable.
Adequate lightning.
Adequate ventilation to minimize the possibility of air currents.
Adequate electrical service for laboratory equipment.
Adequate sink areas with running hot and cold water service.
Laboratory access is restricted to minimize foot traffic by non-laboratory personnel.
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Microbiology Laboratory Equipment General Recommendations:
Have a master list of equipment requiring calibration and preventative maintenance. All equipment needs to be maintained and routinely calibrated according to manufacturers directions.
Each piece of equipment should have either a maintenance logbook or electronic file containing service reports with the following information: Date of service. What was repaired? Was re-calibration necessary?
Calibration stickers – should be present on certain pieces of equipment to aid when calibration is required and contain the following information: Equipment Type Serial or Identification Number Date of Calibration Calibrator’s name or Initials Next Scheduled date of Calibration
Malfunctioning equipment or out-of-calibration equipment needs to be labeled, removed from service until repairs have been made and re-calibration has been performed.
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Laboratory Equipment – Autoclaves/Sterilizers Initially Installed:
Installation Qualification (IQ)
Operational Qualification (PQ)
Performance Qualification: Heat distribution studies of an empty chamber
Heat distribution and penetration studies of typical loading patterns for the chamber.
Routine Annual Calibration of: Temperature Recorders
Pressure Gauges
Timers
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Laboratory Equipment – Incubators/Refrigerators/Freezers
Qualification Installation Qualification
Operational Qualification
Performance Qualification
24-hour temperature distribution mapping study of the interior chamber.
Open door test Used to determine how long the unit takes to recover back to the original operating temperature.
Simulated power failure test Used to see how long the temperature of the unit can be maintained without electrical power.
Verification of accuracy of temperature recording charts if present.
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Laboratory Equipment - Balances
Balance Calibration Each balance needs to be calibrated at least once per year. Reference weights for balance calibration should cover the operating range of the balance (e.g. 1, 10,
25, 100, 500 and 1000 grams) Each reference weight used for calibration should have been calibrated against an National Institute of
Standards and Technology (NIST) or equivalent standard. Confirm accuracy of the balance to +/- 0.1 grams
Weekly Weight Balance Calibration Check Purpose is to detect when a balance starts to be out of calibration by using a NIST or equivalent
standard balance weight.
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Laboratory Equipment – Biological SafetyCabinets/Class 100 or ISO 5 Laminar Flow Hoods
Recommended that each Biological Safety Cabinet and Laminar Flow Hood should calibrated once
per year for:
Biological Safety Cabinets, Class II, Type A2 Requirements Minimum Intake Air: 100 FPM
Downward Air Flow: 50-60 FPM Dispersed Oil Particulate (DOP) Leak Test: Less than 0.01% of DOP particles >0.3 microns in diameter Germicidal Light – verification that the UV lamp is producing the necessary wavelength
Laminar Flow Hood Requirements Airflow Test: 90 FPM +/- 20%
Dispersed Oil Particulate (DOP) Leak Test: Less than 0.01% of DOP particles >0.3 microns in diameter Particle Count Test: Not more than 100 particles of >0.5 microns per cubic foot or not more than 3520
particles of >0.5 microns per cubic meter.
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Laboratory Equipment - Centrifuges Recommended to be calibrated once per year for:
Temperature – if the temperature of the unit is controlled by refrigeration
Rotor Speed
Timer
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Laboratory Equipment – pH Meters
Recommendations: pH meters need to be calibrated and standardized on either a daily basis or when used.
Need to use at least 2 certified pH buffer solutions that is closest to the expected
pH range of the test sample.
Certified buffer solutions must be standardized against an NIST or equivalent
reference.
pH buffer solutions should not be used past their expiration date.
Taking the pH of prepared microbial growth media:
Microbial growth agar – flat bottom pH electrode
Liquid microbial growth media (e.g. broths) – standard pH electrode
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Laboratory Equipment – Microbial Identification Systems
Semi-automated and automated microbial identification systems (e.g.
phenotypic, phylogenetic and genotypic)
Installation Qualification
Operational Qualification
Performance Qualification
Use both know pedigree (ATCC) and wildtype microbial strains.
Conducted identification of microbial strains at 3 separate times by using different individuals.
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Laboratory Equipment – Temperature Monitors
The following temperature monitoring devices need to be calibrated
on at least an annual basis:
Thermometers
Temperature Recording Charts (Fixed and Portable)
Wireless Temperature Data Loggers
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Laboratory Equipment – Media Dispensers
Media dispensers (e.g. pumps, syringes) are commonly used within
Microbiology Laboratories to dispense volumes of microbial count diluents
and liquid microbial growth media into bottles, test tubes or dilution blanks.
Need to be calibrated by using appropriate sized graduate cylinders before
and after to ensure that accurate and consistent quantities are delivered
throughout the dispensing process.
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Laboratory Equipment - Spectrophotometers Spectrophometers are mostly used to prepare microbial inoculums for use in
preservative challenge, MIC/MLC and validation testing.
Calibration Recommendations: Daily or weekly usage:
Use curvettes containing 0.85% Saline Solution and Crystal Violet Gram Stain to adjust
the unit to 0 and 100% light transmittance before conducting a turbidity determination
of a microbial suspension.
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Laboratory Equipment – Water Activity Instruments
Calibration recommendations: Perform on each day of use.
Need to use 2 fresh certified standard water activity salt solutions One salt solution should have a water activity reading below the expected water activity reading of the
test sample.
The second salt solution should have a water activity reading that is above the expected water
activity reading of the test sample.
Expired salt solutions should not be used to take a water activity reading of a test sample.
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Laboratory Equipment – Pippetters
2 Types of Pippetters: Micro-pippetter (e.g. Dispenses a volume of 1 to 10 microliters).
Macro-pippetter (e.g. dispenses a volume of 0.1 to 2.0 milliliter).
Each Type of Pippetter should be calibrated for: Accuracy Percent
Precision Percent
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Laboratory Equipment - Microscopes Conducted maintenance on a microscope must be documented.
Each of the following items of a microscope should be inspected on an annual basis:
Lenses
Alignment
Mechanical Aspects
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Laboratory Equipment – Mechanical Air Samplers
Can be used to determine the microbial bioburden of air samples at various locations
within a Microbiology Laboratory and manufacturing facility.
Annual Calibration Recommendations: Timer of the unit needs to be calibrated so that the correct air volume is sampled.
If mechanical air sampler is used to determine the microbial bioburden of compressed air, the air
flow regulator will need to be calibrated.
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Laboratory Equipment – Water Treatment System
Used to produce the desired grade of water (distilled or deionized) for use in
preparing microbial media and count diluents.
Should be periodically monitored for producing the desired microbial and chemical
quality attributes:
Microbial Attributes <100 CFU/milliliter
Chemical Attributes Total Organic Carbon (TOC): <500 parts per billion (ppb) [µg/liter].
Conductivity at 25oC: <1.3 µS/cm
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Microbial Culture Maintenance
Need to Verify Laboratory Microbial Culture Maintenance Program such as:
How is the laboratory storing and maintaining microbial cultures?
Are each of the microbial cultures that are used within the laboratory passed or purchased from a
vendor (e.g. microbial suspensions, culture sticks or loops) for no more than 5 passages from the
original ATCC vials?
Is proper documentation available indicating that each microbial strain being used within the
laboratory been identified to the genus/species level by either phenotypic, phylogenetic or genotypic
means?
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Microbial Growth Media - Commercially Prepared Each received lot of prepared microbial growth media should have a Certificate of Analysis (COA) with the following
information:
Manufacturers Name and Address of Preparation Facility.
Expiration Date
pH Check
Sterility Check
Microbial Growth Promotion Data.
Each receipt of a commercially prepared lot of microbial growth media should be re-checked for the following to verify
that the shipping process did not have an adverse effect:
pH Check
Confirmation of Sterility
Microbial Growth Promotion
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Microbial Growth Media – Prepared In-HousePrepared In-House: Dehydrated Microbial Growth Media Suggestions:
Each container of dehydrated microbial growth media be labeled with the following: Date Received
Date Opened
Dehydrated microbial growth media containers within the laboratory follow FIFO practices (First In,
First Out).
Containers of dehydrated microbial growth media and supplements are stored according to
manufactures directions.
Expired dehydrated microbial growth media containers need to be discarded to prevent usage.
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Microbial Growth Media – Prepared In-House (Continue)
Prepared In-House : Rehydration and Sterilization Suggestions Proper type of water (e.g. distilled or deionized water) is used to rehydrate microbial growth media.
Each batch of microbial growth media should have a batch record: Name of Media
Date of Preparation
Manufacturers Lot Number
Expiration Date
Quantity of Each Ingredient Weighed
Quantity Prepared
Signature of Preparer
Volume Dispensed
Date of Sterilization
Sterilizer Identification and Run Number
Each batch record is reviewed for accuracy and approved by laboratory
supervisor.
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Microbial Growth Media – Prepared In-House
After sterilization before use in microbial testing, each prepared
batch of microbial growth media should be checked for the following:
pH Check
Confirmation of Sterility
Microbial Growth Promotion Testing
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Storage and Expiration Dating of Laboratory Prepared Microbial Growth Media
Batches of prepared microbial growth media should be stored under conditions
recommended by the vendor.
Microbial growth promotion studies be conducted to verify storage condition and aged
of the microbial growth medium did not affect its ability to support the growth of
microorganisms.
Growth Promotion Studies of Freshly Prepared vs. Aged Microbial Growth Media.
Weight Comparison Studies of Freshly Made to Aged Microbial Growth Agar Petri Dishes.
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Microbial Count Diluents Each batch of microbial count diluents should have an individual batch record with the following information:
Name of Microbial Count Diluent
Date of Preparation
Manufacturers Lot Number of Ingredients Used in the Diluent
Quantity of each ingredient weighed
Quantity Prepared
Signature of the Preparer
Volume Dispensed
The Number of Units Dispensed.
Each batch record is reviewed for accuracy and signed by laboratory supervisor.
After sterilization, each batch of microbial count diluent should be checked to confirm sterility.
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Chemicals and Biochemical Reagents
Includes such things as Gram stain reagents, Oxidase, Coagulase, Catalase, etc.
Checked for their expiration date prior to usage.
Expired materials should not be used in the conductance of microbial testing.
Specificity of each new lot of biochemical reagent should be checked prior to usage or at the same time
with an unknown microbial isolate by using positive and negative microbial controls:
Examples:
Gram Stain Reagents: S. aureus ATCC 6538 and Escherichia coli ATCC 8739
Coagulase Test: S. aureus ATCC 6538 and S. epidermidis ATCC 12228.
Oxidase Test: Ps. aeruginosa ATCC 9027 and Escherichia coli ATCC 8739
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Microbial Biochemical Identification Cards/Kits and Reagents
To determine as to whether shipping conditions had not or had an adverse effect
on the accuracy of an identification call for a microbial isolate, the following
practices is recommended:
Biochemical Identification Cards or Kits (Phenotypic) Each receipt should be tested by using the recommended Quality Control test microorganisms by the
manufacturer.
Extraction and Sequencing Reagents for 16S or 23S rRNA Analysis (Phylogenetic) Each receipt of reagents should be tested by using known pedigree (e.g. ATCC) strains of bacteria,
yeast and mold.
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Microbial Test Procedures Microbial Content Test Methods
Enumeration
Enrichment
Preservative Challenge Test Methods
Environmental Test Methods
Ambient Air
Compressed Air
Environmental Surfaces
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Microbial Content – Enumeration Plate
Count Test Method
GENERAL ASPECTS
Plate Count Neutralizing
Diluent
1:10 Dilution Dispense
&
Incubate
Count Number of Microorganisms/gram or ml
Sample
Microbial Content -Enrichment Test Method
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GENERAL ASPECTS
1.0 or 10.0 grams
Microbial Enrichment
Broth with
Neutralizers
Streak onto Selective/
Differential Microbial Growth Agars
Incubate
Gram-stain and Identify Recovered Microbial Isolates
Sample
Preservative Challenge Test Method
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GENERAL ASPECTS
Standardized Microbial
Suspension
Inoculated Product
Removal of 1.0 gram
Aliquots at Specified Intervals
Neutralization of Preservative Antimicrobial
Activity
Recovery of Surviving
Microorganisms
Calculation of Percent or Log10
Reduction
Microbial Content Test Methods - Validation Enumeration (Plate Count)
Test Microorganisms: Pseudomonas aeruginosa ATCC 9027 Staphylococus aureus ATCC 6538 Candida albicans ATCC 10231 Escherichia coli ATCC 8739 Burkholderia cepacia ATCC 25416 Aspergillus brasiliensis ATCC 16404
Level of Inoculation: Approximately <100 CFU/gram
Enrichment Test Microorganisms:
Ps. aeruginosa ATCC 9027 S. aureus ATCC 6538 C. albicans ATCC 10231* E. coli ATCC 8739 B. cepacia ATCC 25416 Salmonella enterica subsp. enterica servor Typhimurium ATCC 14028**
* Cosmetics, ** Ingestible Non-sterile drug products and dietary supplements
Level of Inoculation: 10 to 100 CFU/0.1 milliliter
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Preservative Challenge Test Method - Validation Test Microorganisms:
Pseudomonas aeruginosa ATCC 9027
Escherichia coli ATCC 8739
Staphylococus aureus ATCC 6538
Burkholderia cepacia ATCC 25416
Candida albicans ATCC 10231
Aspergillus brasiliensis ATCC 16404
Level of Inoculation: Approximately <100 CFU/gram
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Validation of Microbial Enumeration Plate Count and Preservative Challenge Test Method
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GENERAL ASPECTS
Prepare a 104
CFU/ml Suspension
1g + 8.9 ml Neut. Diluent
9.9 ml of
Neut. Diluent
0.1 ml
(<1000 CFU)
0.1 ml (<1000 CFU)
2 x 1.0 aliquots
2 x 1.0 aliquots
Incubate
Count # of microbial colonies
per Petri dish, average counts, convert average counts to Log10
values, and compare
Add to separate
100 x 15 mm Petri Dishes
and add 18 to 20-ml/Petri
Dish of melted
Microbial Growth Agar,
mix, and solidify.
(<100 CFU)
Example of Microbial Count/Preservative Challenge Validation Test Data for a Non-sterile Cream Product Formulation
Test Organism Microbial Counts with Sample
Microbial Counts without Sample
Log10 Value of Counts with Sample
Log10 Value of Counts with Sample
Log Difference
Counts Ave. Counts Ave.
Ps. aeruginosa ATCC 9027
122, 172 147 209, 190 199.5 2.17 2.3 (+) 0.13
S. aureus ATCC 6538
72, 90 81 92, 91 91.5 1.91 1.96 (+ ) 0.05
E. coli ATCC 8739
78, 90 84 81, 93 87 1.92 1.94 (+) 0.02
B. cepacia ATCC 25416
25, 35 30 28, 40 34 1.48 1.53 (+) 0.05
C. albicans ATCC 10231
8, 5 6.5 15, 9 12 0.81 1.08 (+) 0.27
A. brasiliensis ATCC 16404
54, 68 61 44, 47 45.5 1.78 1.65 (-) 0.13
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Validation of an -Enrichment Test Method
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GENERAL ASPECTS
1.0 or 10.0 grams
Microbial Enrichment
Broth with
Neutralizers
Streak onto or Inoculate Selective/
Differential and Non-selective
Microbial Growth Broths/Agars
Incubate
Gram-stain and Identify Recovered Microbial Isolates
Sample
10-100 CFU/0.1 ml
Inoculum
For each test microorganism
Types of Microbial Growth Broths and Agars for Validation of an Enrichment Broth Test Method
Enrichment Broths
Soybean-Casein Digest Medium with 4% Tween 20 and 0.5% Soy Lecithin (USP Section 62)
Modified Letheen Broth (FDA Bacteriological Analytical Manual – Cosmetics)
Eugon LT 100 Broth (ISO Microbial Methods for Cosmetics)
D/E Neutralizing Broth
Selective/Differential and Non-Selective Microbial Growth Broths/Agars
Cetrimide (FDA BAM, ISO and USP) or Pseudomonas Isolation Agar – Ps. aeruginosa
MacConkey Broth and Agar (USP) /MacConkey Agar (FDA BAM)/ MacConkey Agar and Levine EMB Agar (ISO) – E. coli
Vogel Johnson Agar (FDA BAM-Optional) /Mannitol Salt Agar (USP)/Baird-Parker Agar (FDA BAM and ISO) – S. aureus
MacConkey Agar and Soybean-Casein Digest Agar Medium – B. cepacia
Rappaport Vassiladis Salmonella Enrichment Broth and XLD Agar (USP) – Salmonella
Reinforced Medium for Clostridia and Columbia Agar (USP) and Modified Letheen Agar/5% SBA [Anaerobic] (FDA BAM) – Clostridia
Sabouraud Dextrose Agar (ISO) – C. albicans
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Environmental Monitoring - Air
Ambient Air – certain sites within a laboratory and manufacturing facility can pose a risk in causing microbial contamination of susceptible raw ingredients, bulk finished product and finished stock.
Is there a written program including a map of air sampling sites and frequency?
What is the microbial air sampling method? Gravity Settling Plates
Mechanical Air Sampler
Are microbial identifications conducted on recovered representative microbial colonies?
Are the microbial test results trended for each air sampling site?
Compressed Air – is susceptible to microbial contamination because it is stored under humid conditions.
If being sampled, what is the compressed air sampling method?
What is the frequency of compressed air sampling?
Are microbial identifications conducted on recovered representative microbial colonies?
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Environmental Sampling – Sanitization of Equipment Surfaces
Is there a written program including identification of sampling sites for each piece of equipment?
What is the microbial sampling method?
Swabbing (e.g. Calcium alginate swabs or cotton swabs)
Rinse water analysis
Contact microbial growth agar plates
Is there proper neutralization of sanitizer/disinfectant residues if chemical sanitization is used?
Are representative recovered microbial colonies being identified to the genus/species level?
What is the microbial test criteria for each sampling site in a piece of equipment?
Is it appropriate for the type of microbial test specifications for the product being manufactured?
46
Purified Water Systems
Laboratory Purified Water System
Facility Purified Water System with an Outlet in the Microbiology
Laboratory
Is there a current engineering drawing present of the facility purified water system? Need to verify that each of the components of the system indicated on the drawing has been installed.
Has a validation been conducted? Installation Qualification
Operational Qualification
Performance Qualification
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Microbial Testing of Purified Water Systems
What is the frequency of microbial testing (e.g. once per week or several
times a week)?
Are purified water samples aseptically collected?
Microbial Test Method Is the method membrane filtration or plate count?
What type of microbial growth agars are being used (e.g. R2A or Plate Count Agar)?
What is the Incubation temperature and time of incubation?
Are recovered microbial isolates identified to the genus/species level?
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Documentation
Purpose:
Provides a written record of the activities that occurs within the laboratory such as:
Training
Standard Operating Procedures
Microbial Test Methods
Microbial Test Results
Provides an operational history of the laboratory.
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Documentation – Records and Reports
Logbook, Worksheet, or Laboratory Information Management System (LIMS) Complete microbial test data must be present to show compliance with established
specifications and standards. Description of the test ample received for testing.
Source
Quantity
Lot Number
Date sample taken
Date sample was received for testing
A statement of each test method used.
Statement of sample weight or measure used for each microbial test.
A statement of microbial test result conformance with specification (Pass/Fail).
Initials/signature of the person who conducted the microbial test for a sample with date of performance.
Initials/signature of person who conducted review for accuracy (Second person for review).
Good Documentation Practices – Microbial Test Methods/Standard Operating Procedures
Is each microbial test method scientifically based (e.g. compendia or guideline)?
Is each Standard Operating Procedure/microbial test method written in a clear and
concise manner?
Is there a secondary ‘qualified” reviewer for each issued Standard Operating
Procedure/microbial test method?
Are written Standard Operating procedures and microbial test methods periodically
review and updated as necessary to document any changes?
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Good Documentation Practices – Laboratory Forms
Are laboratory forms for Standard Operating Procedures/microbial test methods standardized and
controlled?
Are errors/cross-outs on laboratory forms properly documented (e.g. initials of person with date
[mmddyy])?
Do not contain extraneous marks or strange comments?
Are laboratory forms periodically updated to reflect any changes that have occurred in a Standard
Operating Procedure or microbial test method?
52
Good Documentation Practices - Logbooks
Are errors/cross-outs initialed and dated?
Are logbook reviews conducted in a timely manner?
53
Documentation - Discrepancies
Any discrepancies in equipment and microbial test results for raw
ingredients, finished products and environmental test samples
should be:
Investigated
Documented
Evaluated by appropriate personnel
54
Documentation - Deviations
A minor change could invalidate a test method.
Any deviation must be recorded and justified
Written specifications
Standards
Sampling plan
Microbial test methods or other laboratory control measures.
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Documentation - Investigations
Is there a formalized out-of-specification investigation procedure for microbial
test results?
Purpose of this procedure:
To establish a root cause for each microbial test result failure.
Helps to institute corrective actions to prevent a future identical microbial test result failure.
Does this investigation procedure contain the following steps?
Process defined
Detail the findings of the investigation
Reporting of results
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Conclusions
57
Thank You
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